What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2023-03-08 compared with 2022-03-09 · 576 added, 587 removed, 1640 unchanged (41% of the section changed)

1 unchanged sentence

Our approach is based on the central premise that we can learn from patients who are winning their fight against cancer in order to treat those who are not.

Using one of our proprietary platform technologies, TargetScan, we analyze the T cells of cancer patients with exceptional responses to immunotherapy to discover how the immune system naturally recognizes and eliminates tumor cells in these patients.

This allows us to precisely identify the targets of T cell receptors, or TCRs, that are driving these exceptional responses.

We are continuing to build our ImmunoBank, a repository of therapeutic T cell receptors, or TCRs, that recognize diverse targets and are associated with multiple human leukocyte antigen, or HLA, types to provide customized multiplexed TCR-T therapy candidates for patients with a variety of solid tumors.

We are building our ImmunoBank using our proprietary platform technologies.

Using TargetScan, we analyze the T cells of cancer patients with exceptional responses to immunotherapy to discover how the immune system naturally recognizes and eliminates tumor cells in these patients.

This allows us to precisely identify the targets of TCRs that are driving these exceptional responses.

We aim to use these anti-cancer TCRs to treat patients with cancer by genetically engineering their own T cells to recognize and eliminate their cancer.

1 unchanged sentence

We reduce the risk and enhance the safety profile of these therapeutic TCRs by screening them using SafetyScan to identify potential off-targets of a TCR and eliminate those TCR candidates that cross-react with proteins expressed at high levels in critical organs.

We believe this three-pronged approach will enable us to discover and develop a wide array of potential treatment options for patients with cancer.

We are advancing a robust pipeline of TCR-T therapy candidates for the treatment of patients with hematologic and solid tumor malignancies.

Our lead liquid tumor product candidates, TSC-100 and TSC-101, are in development for the treatment of patients with hematologic malignancies to eliminate residual leukemia and prevent relapse following hematopoietic stem cell transplantation, or HCT.

Our in-house good manufacturing practices, or GMP, manufacturing platform, which we refer to as T-Integrate, enables the rapid, cost-effective and consistent manufacturing of TCR-Ts.

Our TCR-T therapy candidates are manufactured using a non-viral transposon/transposase system.

This system is highly reproducible and can be routinely manufactured in a cost-effective manner without the need for extensive process development.

The additional cargo capacity of our non-viral vector delivery system allows us to add additional T cell enhancements to our product candidates to provide support for cytotoxic T cells.

By adding CD8α/β, we believe we have the potential to increase response to TCR-T therapy up to four-fold in the clinic compared to the addition of the TCR alone.

We are also adding dominant-negative TGFβRII to enable T cell proliferation despite the presence of TGFβ

in the hostile tumor microenvironment, potentially enhancing T cell persistence.

Our GMP facility has the capacity to manufacture clinical trial materials for more than 300 patients per year, sufficient to support our programs through Phase 2 clinical development.

We are advancing a robust pipeline of TCR-T therapy candidates for the treatment of patients with hematologic malignancies and solid tumors.

Our lead product candidates, TSC-100 and TSC-101, are in development for the treatment of patients with hematologic malignancies to eliminate residual leukemia and prevent relapse following hematopoietic cell transplantation, or HCT.

TSC-100 and TSC-101 target HA-1 and HA-2 antigens, respectively, which are well-recognized TCR targets that were identified in patients with exceptional responses to HCT-associated immunotherapy.

We submitted Investigational New Drug, or IND, applications with the U.S.

Food and Drug Administration, or FDA, for each of TSC-100 and TSC-101 in the fourth quarter of 2021.

The FDA has cleared the IND for TSC-100 while the IND for TSC-101 remains on clinical hold pending additional assessment of the potential for off-tumor reactivity in certain tissues.

We plan to initiate the Phase 1 clinical study of TSC-100 in the first half of 2022.

Pending clearance of the IND for TSC-101, we will initiate the TSC-101 arm of the trial.

We have initiated a multi-arm Phase 1 clinical study of TSC-100 and TSC-101 with several clinical sites activated, with planned additional sites to be added in 2023.

In addition, we are developing multiple TCR-T therapy candidates for the treatment of solid tumors.

One of the key goals for our solid tumor program is to develop what we refer to as multiplexed TCR-T therapy.

We are designing these multiplexed therapies to be a combination of up to three highly active TCRs that are customized for each patient and selected from our bank of therapeutic TCRs, which we refer to as ImmunoBank.

We plan to populate the ImmunoBank with TCRs for multiple targets as well as multiple HLA types for each target, thus helping us to overcome the key solid tumor resistance mechanisms of target loss as well as HLA loss.

We are currently advancing five solid tumor programs:

TSC-200 in IND-enabling activities;

TSC-204 advancing to IND-enabling studies;

and TSC-201, TSC-202, and TSC-203, in lead optimization.

We expect to submit two IND applications for our solid tumor TCR-T therapy candidates in the second half of 2022, with additional IND applications expected to be submitted in 2023.

We plan to populate the ImmunoBank with TCRs for multiple targets as well as multiple HLA types for each target, thus helping us to overcome key solid tumor resistance mechanisms of target loss and HLA loss.

We are currently advancing six solid tumor programs:

TSC-204, entering Phase 1 development;

TSC-200 and TSC-203, in IND-enabling activities;

TSC-201, in lead optimization;

and TSC-202 and TSC-205, in discovery.

In December 2022, we submitted a primary investigational new drug, or IND, application for T-Plex, enabling customized mixtures of TCR-Ts to be administered to patients based on cancer-targets and associated common HLA types expressed in their tumors, as well as secondary IND applications for two initial TCR-T product candidates:

TSC-204-A0201 and TSC-204-C0702.

The FDA has cleared our IND applications for T-Plex, TSC-204-A0201, and TSC-204-C0702, allowing us to initiate study start-up activities.

We plan to further expand the ImmunoBank by filing INDs for additional TCRs throughout 2023.

T cells are an essential component of the adaptive immune system and provide protection against cancer, infection, and autoimmune disease.

2 unchanged sentences

If their TILs do not have appropriate anti-cancer specificities, the therapy is unlikely to be effective.

In addition, TIL therapy has, to date, shown limited applicability for the treatment of liquid tumors.

In addition, TIL therapy has, to date, shown limited applicability for the treatment of hematologic malignancies.

In contrast, CAR-T therapy has proven effective in certain hematological malignancies of lymphoid origin but have not yet shown efficacy or safety in myeloid malignancies.

Additionally, this type of treatment is limited to targets on the surface of tumor cells and has not yet been shown to effectively penetrate solid tumors.

Both TIL and CAR-T therapies, as well as other immunotherapies such as checkpoint inhibitors, harness the power of cytotoxic T cells in fighting cancer.

Additionally, this type of treatment is limited to targets on the surface of tumor cells and carries higher toxicity risks such as cytokine release syndrome compared with TCR-T therapy due to the CAR-T therapy's artificial intracellular signaling domains and excessive stimulation of T cells.

Both TIL and CAR-T therapies,

as well as other immunotherapies such as checkpoint inhibitors, harness the power of cytotoxic T cells in fighting cancer.

Despite demonstrating compelling efficacy, they are only effective in a subset of patients.

To address a broader patient population, we believe additional T cell-based approaches are needed that more closely mimic the way the immune system recognizes and fights cancer in patients who are responding to immunotherapy.

Two key shortcomings in the TCR field remain:

Low response rates, and limited duration of response.

These shortcomings are related to solid tumors being heterogenous, and poor persistence of engineered T cells in patients.

We believe we can overcome these known issues by adding enhancements to our product candidates, such as the addition of CD8α/β

to improve persistence compared to CD8α

We are also co-introducing DN-TGFβRII, which is designed to overcome immunosuppression from TGFβ

in the tumor microenvironment.

Our decision to develop TCR-T therapies for the treatment of cancer is based on our conviction that we can learn from the natural interaction between T cells and tumor cells and harness this information to treat patients by reprogramming their immune systems.

10 unchanged sentences

Our TCR-T therapies are designed to be used in combination with each other.

We are building our diverse ImmunoBank of TCRs to allow for multiplexed TCR-T therapy, which has the potential to address the heterogeneous nature of solid tumors and to prevent resistance developing due to loss of a single target.

We are building the ImmunoBank of TCRs to allow for multiplexed TCR-T therapy, which has the potential to address the heterogeneous nature of solid tumors and to prevent resistance developing due to loss of a single target.

We believe this approach may allow us to overcome the limitations and challenges of TCR-T therapy development to date.

We plan to populate ImmunoBank with TCRs for multiple targets as well as multiple HLA types for each target, thus helping us to overcome the key solid tumor resistance mechanisms of target loss as well as HLA loss.

We plan to populate the ImmunoBank with TCRs for multiple targets as well as multiple common HLA types for each target, thus helping us to overcome the key solid tumor resistance mechanisms of target loss as well as HLA loss.

Our approach is expandable.

ImmunoBank has the flexibility to be used with new and optimized methods of T cell engineering that we may develop over time.

We are building ImmunoBank to be compatible with both autologous and allogeneic engineering technologies in order to potentially transition to generating off-the-shelf, allogeneic T cells that have been pre-engineered with our TCRs for direct administration to patients.

The ImmunoBank has the flexibility to be used with new and optimized methods of T cell engineering that we may develop over time.

We are building the ImmunoBank to be compatible with both autologous and allogeneic engineering technologies in order to potentially transition to generating off-the-shelf, allogeneic T cells that have been pre-engineered with our TCRs for direct, customized administration to patients.

As we expand the ImmunoBank to include TCRs across additional targets and HLA types, we believe we will increase the eligible patient population for our clinical trials, which will allow for rapid and efficient clinical trial enrollment with fewer screen failures.

Our proprietary platform is designed to:

3 unchanged sentences

(iv) identify off-targets of TCRs to eliminate candidates that could potentially pose a safety risk;

and (v) manufacture TCR-T therapies efficiently and consistently without the use of viral vectors using our T-Integrate technology.

The central elements of our platform that differentiate us from other cell therapy companies are TargetScan, ReceptorScan, SafetyScan, ImmunoBank and T-Integrate.

and (v) manufacture TCR-T therapies efficiently

and consistently without the use of viral vectors using our T-Integrate technology.

The central elements of our platform that differentiate us from other cell therapy companies are TargetScan, ReceptorScan, SafetyScan, the ImmunoBank and T-Integrate.

At the core of our proprietary platform is TargetScan, which enables us to identify natural targets of TCRs using an unbiased, genome-wide high-throughput screen.

1 unchanged sentence

It can be applied to virtually any TCR that plays a role in the cause or prevention of disease.

Using TargetScan, we have identified more than 60 shared antigens in patient tumors, and over 90% of these targets have not previously been publicly identified as targets for TCR-T therapy.

Using TargetScan, we have identified about 100 novel antigens as targets of tumor infiltrating T cells from patients who are actively responding to immunotherapy.

We believe this provides us with a competitive advantage, because not only are we among the first to identify these targets as tumor-specific antigens, but also we have already identified highly active TCRs that recognize these targets.

7 unchanged sentences

Our novel technologies allow us to gene-synthesize hundreds of TCRs simultaneously and to rapidly sort through hundreds of target-specific TCRs in a single high-throughput screen to identify the most active clones.

Using ReceptorScan, we have identified our two lead TCR-T therapy candidates, TSC-100 targeting HA-1 and TSC-101 targeting HA-2, as well as our other pipeline programs.

We are building ImmunoBank, our diverse bank of therapeutic TCRs, to allow for multiplexed TCR-T therapy, which has the potential to address the heterogeneous nature of solid tumors and to prevent resistance developing due to loss of a single haplotype target.

Using ReceptorScan, we have identified our two lead TCR-T therapy candidates, TSC-100 targeting HA-1 and TSC-101 targeting HA-2, as well as our other pipeline programs such as the MAGE-A1-targeting TCR that has now become our solid tumor therapeutic candidate, TSC-204-C0702, featured in the peer-reviewed journal Cell in 2022.

We are building the ImmunoBank, our diverse bank of therapeutic TCRs, to allow for multiplexed TCR-T therapy, which has the potential to address the heterogeneous nature of solid tumors and to prevent resistance developing due to loss of a single haplotype target.

We believe this approach may allow us to overcome the limitations and challenges of TCR-T therapy development to date.

Finally, we are building ImmunoBank to have the flexibility to be used with new and optimized methods of T-cell engineering that we may develop over time.

Finally, we are building the ImmunoBank to have the flexibility to be used with new and optimized methods of T cell engineering that we may develop over time.

Manufacturing cell therapies is highly complex, and associated challenges have led to significant delays or failures in the development of many cell therapies.

5 unchanged sentences

Unlike lentivirus, both of these components are routinely manufactured in a cost-effective manner without the need for extensive process development.

We have completed the construction and validation of a 7,000 square-foot state-of-the-art good manufacturing practices, or GMP, manufacturing facility to manufacture all necessary Phase 1 and 2 supply for our TCR-T therapies.

We expect that this facility will provide sufficient production capacity to supply product for all planned Phase 1 and 2 clinical studies for the liquid and solid tumor programs.

Approval of our IND for TSC-100 validates our facility for human manufacturing of our T cell therapies.

We have completed the construction and validation of a 7,000 square-foot state-of-the-art GMP manufacturing facility to manufacture all necessary Phase 1 and 2 supply for our TCR-T therapies.

We expect that this facility will provide sufficient production capacity to supply product for all planned Phase 1 and 2 clinical studies for the hematologic malignancies and solid tumor programs.

Clearance of our INDs for TSC-100 and TSC-101 validates our facility for human manufacturing of our T cell therapies.

We believe our manufacturing platform will enable us to efficiently develop and manufacture many different TCR-T therapies, allowing us to deliver customized multiplexed therapy to patients with cancer.

We are building ImmunoBank with the goal of delivering customized multiplexed TCR-T therapies to a wide range of patients with cancer.

In addition, we are applying our platform to identify targets and TCRs in therapeutic areas outside of oncology, such as

autoimmune disorders and infectious disease, through strategic partnerships.

As of February 28, 2023, we have successfully manufactured TSC-100 and TSC-101 but have not yet dosed patients in our hematological malignancies program.

The FDA has additionally cleared three INDs for our solid tumor program, including our primary IND, T-Plex which supports the simultaneous use of multiple TCRs to create customized, multiplexed TCR-T therapy candidates, as well as INDs for TSC-204-A0201 and TSC-204-C0702, in our view further validating our manufacturing capabilities.

We are building the ImmunoBank with the goal of delivering customized multiplexed TCR-T therapies to a wide range of patients with cancer.

In addition, we are applying our platform to identify targets and TCRs in therapeutic areas outside of oncology, such as autoimmune disorders and infectious disease, through strategic partnerships.

Our current proprietary pipeline is summarized in the figure below.

In addition to our proprietary pipeline programs noted above, we have also entered into collaborations with strategic partners for applications of our platform technologies.

We have a collaboration and license agreement with Novartis Institutes for BioMedical Research, Inc., or Novartis, to identify novel cancer antigens from the T cells of patients with a certain specific type of cancer.

We have a collaboration and license agreement with Novartis Institutes for BioMedical

Research, Inc., or Novartis, to identify novel cancer antigens from the T cells of patients with a certain specific type of cancer.

Novartis has the option to license and develop therapies for up to three of the targets discovered in the collaboration.

Should Novartis license a target, we are eligible for a payment of $10 million per target as well as future milestones and royalties.

In addition, we have partnered with QIAGEN Sciences, LLC to develop a highly specific diagnostic test to determine prior exposure to SARS-CoV-2 based on the presence of anti-viral T cells.

With our differentiated platform as the foundation, we are building a three-pillar research and development strategy to create transformational TCR-T therapies for patients.

Our Liquid Tumor Program.

We are developing our liquid tumor program to treat patients with hematologic malignancies who are undergoing allogeneic HCT.

Our Hematologic Malignancies Program.

We are developing our hematologic malignancies program to treat patients with non-B cell malignancies including acute myeloid leukemia, or AML, myelodysplastic syndromes.

or MDS, and acute lymphocytic leukemia, or ALL, who are undergoing allogeneic HCT.

In the first phase of our clinical development strategy, we are initially focusing on clinically validated cancer targets that have been discovered in patients with exceptional responses to HCT-associated immunotherapy, including HA-1 and HA-2.

In the fourth quarter of 2021, we submitted IND applications with the FDA for our lead TCR-T therapy candidates, TSC-100 and TSC-101.

The FDA cleared the IND for TSC-100 in January 2022, while the IND for TSC-101 remains on clinical hold.

For TSC-101, we received written communication from the FDA asking for additional assessment of the potential for off-tumor reactivity in certain tissues and are working with the agency to resolve its questions as quickly as possible.

The liquid tumor trial is based on an umbrella protocol, which will allow us to begin the TSC-100 and control arms of the trial in the near term and to open the TSC-101 arm to the ongoing trial upon clearance of the IND.

We plan to initiate the Phase 1 clinical study of TSC-100 in the first half of 2022.

Pending clearance of the IND for TSC-101, we will then initiate the TSC-101 arm of the trial, allowing for us to advance TSC-100 into Phase 1 clinical trials.

In the first and second quarter of 2022, the FDA cleared the INDs for TSC-100 and TSC-101, respectively.

We have initiated a multi-arm Phase 1 clinical study with several clinical sites activated with planned additional sites to be added in 2023.

The study protocol allows us to conduct clinical trials of TSC-100 and TSC-101 in parallel, with patients enrolled in treatment arms based on their genotype.

1 unchanged sentence

Furthermore, eligible patients will require donors who are negative for either the target antigen or the HLA-A*02:01 allele.

Through the development of our liquid tumor program, we are building a foundation of manufacturing, clinical, and regulatory capabilities, which will be applied to the future development of our broader portfolio of TCR-T therapy candidates for solid tumors.

With the FDA clearance of our IND for TSC-100, we believe our approach has been validated.

Through the development of our hematologic malignancies program, we have built a foundation of manufacturing, clinical, and regulatory capabilities, which we are applying to the development of our broader portfolio of TCR-T therapy candidates for solid tumors.

Our Solid Tumor Program.

1 unchanged sentence

Our TSC-200 series of product candidates are designed to elicit anti-tumor responses in patients by targeting cancer-specific antigens in their tumor cells.

Our TCR-T therapy candidates

Our TCR-T therapy candidates include:

(i) either well-recognized cancer targets that have demonstrated anti-tumor activity in clinical trials or novel targets that were identified by TargetScan from the T cells of patients responding to immunotherapy, and (ii) naturally occurring TCRs specific to a patient’s HLA type that recognize these cancer-specific targets.

Such targets are not only commonly shared among patients with the same cancer type, but also frequently expressed in multiple solid tumor types, enabling clinical development across multiple indications.

Our first five product candidates include a combination of known targets, such as HPV16 for TSC-200, PRAME for TSC-203, and MAGE-A1 for TSC-204, as well as targets that are novel antigens for TCR-T therapy, such as for TSC-201 and TSC-202.

In addition to our five lead product candidates, we have identified over 60 novel antigens based on tumor samples from patients who are actively responding to immunotherapy using our TargetScan technology.

Our first six product candidates include a combination of known targets, such as HPV16 for TSC-200, PRAME for TSC-203, and MAGE-A1 for TSC-204, as well as targets that are novel antigens for TCR-T therapy, such as for TSC-201, TSC-202, and TSC-205.

In addition to our six lead product candidates, we have identified about 100 novel antigens as targets of tumor infiltrating T cells from patients who are responding to immunotherapy using our TargetScan technology.

We are in early stages of analyzing these additional novel antigens and plan to advance those that we believe have the best potential as a TCR-T product candidate into preclinical development.

Our vision is to create and continuously expand ImmunoBank to enable customized multiplexed TCR-T therapy for a wide range of solid tumor patients.

Our vision is to create and continuously expand the ImmunoBank to enable customized multiplexed TCR-T therapy for a wide range of solid tumor patients.

Our initial solid tumor indications include head & neck, cervical, non-small cell lung and ovarian cancers, as well as melanoma.

For each patient with a solid tumor malignancy, we plan to analyze their tumor to determine which targets are expressed at high levels in each patient's particular cancer.

We will then access ImmunoBank and select up to three TCRs that match their HLA type and address the most highly expressed targets in their tumor.

We will then access the ImmunoBank and select up to three TCRs that match their HLA type and address the most highly expressed targets in their tumor.

We will use this set of TCRs to genetically reprogram their T cells to recognize these targets, and the resulting T cells will be infused back into the patient as a multiplexed TCR-T therapy.

We are also adding enhancements to our product candidates to deepen tumor responses and prolong duration of response.

The additional cargo capacity of our non-viral vector delivery system allows us to add additional T cell enhancements to our product candidates to provide support for cytotoxic T cells.

By adding CD8α/β, we believe we have the potential to increase response to TCR-T therapy up to four-fold in the clinic compared to the addition of the TCR alone.

We are also adding dominant-negative TGFβRII to enable T cell proliferation despite the presence of TGFβ

in the hostile tumor microenvironment, potentially enhancing T cell persistence.

Strategic Partnerships and Collaborations.

T cells play a fundamental role in many other therapeutic areas beyond cancer, such as autoimmune disorders and infectious disease.

T cells play a fundamental role in many other therapeutic areas beyond cancer, such as autoimmune diseases and infectious disease.

We believe that our TargetScan technology is well suited to discover novel antigens for the development of therapeutics, diagnostics, and vaccines in these other therapeutic areas.

1 unchanged sentence

Our mission is to create life-changing T cell therapies for patients by unleashing the untapped potential of the human immune system.

Our goal is to use our proprietary platform technologies for the identification of novel tumor-specific antigens and clinically active TCRs to become a leader in the development of engineered T cell therapies for the treatment of liquid and solid tumors.

Our strategy includes the following key elements:

Leverage our proprietary platform technologies to build our diverse ImmunoBank of therapeutic TCRs to treat a wide range of tumor types .

Leverage our proprietary platform technologies to build the ImmunoBank of therapeutic TCRs to treat a wide range of tumor types .

Our TargetScan technology enables us to identify novel antigens that are broadly expressed across multiple types of solid tumors.

1 unchanged sentence

Our platform allows us to assess the specificity and cytotoxicity of these TCRs to develop a portfolio of TCR-T therapy candidates with therapeutic potential.

As we continue to expand our screening technology, we believe we will be able to generate our ImmunoBank of therapeutic TCRs with the diversity required to treat many solid tumors using multiplexed therapy.

Advance our lead liquid tumor product candidates, TSC-100 and TSC-101, through clinical development.

As we continue to expand our screening technology, we believe we will be able to generate the ImmunoBank of therapeutic TCRs with the diversity required to treat many solid tumors using multiplexed therapy.

Advance our lead product candidates, TSC-100 and TSC-101, through clinical development.

Our two lead programs, TSC-100 and TSC-101, are designed to target HA-1 and HA-2, respectively, both of which are antigens with clinically demonstrated anti-tumor effects in patients who naturally develop T cells specific to these targets.

2 unchanged sentences

In the fourth quarter of 2021 we submitted INDs for each of TSC-100 and TSC-101 to the FDA.

The FDA cleared the IND for TSC-100 in January 2022 enabling us to move forward with Phase 1 clinical development, while the IND for TSC-101 remains on clinical hold pending additional assessment of the potential for off-tumor reactivity in certain tissues.

We plan to initiate the Phase 1 clinical study of TSC-100 in the first half of 2022.

Pending clearance of the IND for TSC-101, we will then initiate the TSC-101 arm of the trial.

The FDA cleared the INDs for both TSC-100 and TSC-101 enabling us to move forward with Phase 1 clinical development.

We have initiated a multi-arm Phase 1 clinical study of TSC-100 and TSC-101 with several clinical sites activated, with planned additional sites to be added in 2023.

The study protocol allows us to conduct clinical trials of TSC-100 and TSC-101 in parallel, with patients enrolled in treatment arms based on their genotype.

In addition, through our liquid tumor programs, we have established a foundation of manufacturing, clinical and regulatory capabilities to support the development of our broad portfolio of TCR-T therapies.

Apply experience from our liquid tumor program to efficiently develop our solid tumor program targeting both novel and previously identified antigens.

Using TargetScan, we have identified over 60 novel antigens based on tumor samples from patients who are actively responding to immunotherapy.

We are initially developing our TSC-200 series of TCR-T therapies against five selected target antigens that are frequently expressed across multiple solid tumor types.

Our first five solid tumor TCR-T therapy candidates include a combination of known targets, such as HPV16 for TSC-200, PRAME for TSC-203, and MAGE-A1 for TSC-204 as well as targets that are novel antigens for TCR-T therapy, such as for TSC-201 and TSC-202.

believe that the treatment of solid tumors will require a combination of several TCR-T therapeutics, which we refer to as ‘multiplexed therapy.’

We plan to leverage the foundation built from our liquid tumor programs to efficiently develop a robust portfolio of TCR-T therapy candidates and expand ImmunoBank to enable multiplexed TCR-T therapies for solid tumors.

Continue to develop manufacturing capabilities based on our non-viral T-Integrate system.

In addition, through our hematologic malignancies programs, we have established a foundation of manufacturing, clinical and regulatory capabilities to support the development of our broad portfolio of TCR-T therapies.

Apply experience from our hematologic malignancies program to efficiently develop our solid tumor program targeting both novel and previously identified antigens.

Using TargetScan, we have identified about 100 novel antigens as targets of tumor infiltrating T cells from patients who are responding to immunotherapy.

We are initially developing our TSC-200 series of TCR-T therapies against six selected target antigens that are frequently expressed across multiple solid tumor types.

Our first six solid tumor TCR-T therapy candidates include a combination of known targets, such as HPV16 for TSC-200, PRAME for TSC-203, and MAGE-A1 for TSC-204 as well as targets that are novel antigens for TCR-T therapy, such as for TSC-201, TSC-202, and TSC-205.

We believe that the treatment of solid tumors will require a combination of several TCR-T therapeutics, which we refer to as ‘multiplexed therapy.

We plan to leverage the foundation built from our hematologic malignancies programs to efficiently develop a robust portfolio of TCR-T therapy candidates and expand the ImmunoBank to enable multiplexed TCR-T therapies for the treatment of solid tumors.

Maintain internal manufacturing capabilities based on our non-viral T-Integrate system.

We believe that in-house manufacturing capabilities substantially facilitate the successful early development of cell therapies.

For our TCR-T therapy candidates, we have developed a non-viral gene delivery system, which we refer to as T-Integrate, based on transposons that are designed to enable cost-effective and consistent cell manufacturing with short development times.

We have built an internal, fully operational GMP manufacturing facility that we expect will provide sufficient capacity to support all of our clinical programs in both liquid and solid tumors through Phase 2 clinical trials.

With the FDA clearance of our IND for TSC-100, we believe our approach has been validated.

We have built an internal, fully operational GMP manufacturing facility that we expect will provide sufficient capacity to support all of our clinical programs in both hematologic malignancies and solid tumors through Phase 2 clinical trials.

The additional cargo capacity of our non-viral vector delivery system allows us to add additional T cell enhancements to our product candidates to provide support for cytotoxic T cells.

By adding CD8α/β, we believe we have the potential to increase response to TCR-T therapy up to four-fold in the clinic compared to the addition of the TCR alone.

We are also adding dominant-negative TGFβRII to enable T cell proliferation despite the presence of TGFβ

in the hostile tumor microenvironment, potentially enhancing T cell persistence.

With the FDA clearance of our IND applications for TSC-100, TSC-101, and our first three IND applications for our solid tumor program, we consider our approach to be validated.

Develop next generation T cell engineering capabilities .

Our long-term vision is to build an allogeneic repository of off-the-shelf, genetically engineered T cells and provide multiplexed TCR-T therapies to patients with a wide range of malignancies.

Our long-term vision is to build an allogeneic repository of off-the-shelf, genetically engineered T cells and provide customized multiplexed TCR-T therapies to patients with a wide range of malignancies.

Although our initial solid tumor programs are autologous, we are developing T cell engineering technologies and in-house manufacturing capabilities to transition our therapeutic TCRs to allogeneic therapies based on T cells derived from healthy donors or induced pluripotent stem cells.

1 unchanged sentence

Opportunistically pursue strategic partnerships and collaborations to maximize the full potential of our platform .

Our platform represents a powerful tool to identify targets and TCRs in therapeutic areas outside of oncology, such as autoimmune disorders and infectious disease.

Our platform represents a powerful tool to identify targets and TCRs in therapeutic areas outside of oncology, such as

autoimmune diseases and infectious disease.

We intend to seek strategic partners with proven clinical development and commercialization capabilities for certain targets and/or assets that do not overlap with our internal programs or our core focus.

2 unchanged sentences

Should Novartis license a target, we are eligible for a payment of $10 million per target as well as future milestones and royalties.

Additionally, we have established a partnership for the development of a T cell-based COVID-19 diagnostic with QIAGEN Sciences, LLC.

We have also expanded our target discovery capabilities to include both CD8+ and CD4+ T cell target discovery by engineering our platform to include class II antigen presentation.

This capability allows for us to expand discovery efforts into T-cell mediated autoimmune diseases that have a strong Major Histocompatibility Complexes, or MHC, class II linkage.

We intend to leverage this new capability to identify the pathogenic autoantigens driving T-cell mediated autoimmune diseases.

Background on T Cell Therapies

23 unchanged sentences

MHC proteins, which present different peptides to the human immune system, are highly variable among people.

An individual’s MHC proteins are determined by their Human Leukocyte Antigen, or HLA, type.

An individual’s MHC proteins are determined by their HLA type.

Although there are many different HLA types, some are quite common.

33 unchanged sentences

As a result, only a few dozen targets have been identified to date and most clinical development efforts are focused on a short list of the most promising targets.

Two key shortcomings in the TCR field remain:

Low response rates, and limited duration of response.

These are related to solid tumors being heterogenous, and poor persistence of engineered T cells in patients.

We believe we can overcome these known issues by adding enhancements to our product candidates, such as the addition of CD8α/β

to improve persistence compared to CD8α

We are also co-introducing DN-TGFβRII, which is designed to overcome immunosuppression from TGFβ

in the tumor microenvironment.

Our approach is based on the central premise that we can learn from patients who are winning their fight against cancer in order to treat those who are not.

Using our proprietary platform technologies, we are analyzing the T cells of cancer patients with exceptional responses to immunotherapy to discover clinically relevant targets and TCRs.

We are building ImmunoBank with the goal of delivering customized multiplexed TCR-T therapy to a wide range of patients with cancers.

We are building the ImmunoBank with the goal of delivering customized multiplexed TCR-T therapy to a wide range of patients with cancers.

When a patient responds to an immunotherapy drug such as an immune checkpoint inhibitor, their tumor shrinks because T cells in their tumor become activated and drive an anti-tumor cytotoxic response.

The TCRs of their T cells recognize tumor-specific antigens on tumor cells and signal the T cell to kill the cancer cells.

Our approach starts with isolating clinically active anti-cancer T cells from tumor samples of patients who are actively responding to immunotherapy agents.

Our approach starts with isolating clinically active anti-cancer T cells from tumor samples of patients who are responding to immunotherapy agents.

We then use our proprietary TargetScan technology to determine the precise targets being recognized by their TCRs.

3 unchanged sentences

Furthermore, we have already identified a TCR that recognizes the target and, importantly, is associated with a meaningful clinical response in a patient.

This approach was highlighted in the peer-reviewed journal Cell in 2019 .

To de-risk clinical development of the TCR, we use our SafetyScan technology to scan across every peptide sequence in the entire human proteome with the goal of ensuring that it does not have any problematic off-target effects.

We then select TCRs that are highly active with no apparent problematic off-target effects to be added to ImmunoBank.

We then select TCRs that are highly active with no apparent problematic off-target effects to be added to the ImmunoBank.

In addition to discovering novel TCR/target pairs, we are leveraging our proprietary ReceptorScan technology to identify highly active TCRs against previously identified and clinically validated targets.

This approach was featured in the peer-reviewed journal Cell in 2022.

Once we identify these highly active TCRs, we use our SafetyScan technology to reduce the risk that they exhibit problematic off-target effects, which de-risks their subsequent clinical development.

The diagram below illustrates our proprietary discovery process where therapeutic TCR candidates are discovered using either TargetScan or ReceptorScan and those that we characterize as the best TCRs after screening with SafetyScan are added to ImmunoBank.

Our Proprietary Target and TCR Discovery Process

Our discovery process enables us to build and expand ImmunoBank with what we believe represents the most active TCRs isolated from a large group of diverse patients who are responding to immunotherapy.

Our discovery process enables us to build and expand the ImmunoBank with what we believe represents the most active TCRs isolated from a large group of diverse patients who are responding to immunotherapy.

We are developing TCR-T therapies that use these clinically relevant TCRs to reprogram the T cells of patients who do not spontaneously generate effective anti-cancer T cells and thus do not respond to immunotherapy.

1 unchanged sentence

Next, to manufacture engineered T cells, white blood cells will be obtained from either the patient or a healthy donor using a procedure called leukapheresis.

We will then transport these white blood cells to our in-house manufacturing facility, where we isolate the T cells and genetically engineer them using TCR sequences from ImmunoBank.

We believe the continued expansion and diversification of ImmunoBank will enable us to deliver customized multiplexed TCR-T therapy to patients, where each patient’s T cells are engineered with multiple TCRs that are matched to their specific tumor and HLA type.

We will then transport these white blood cells to our in-house manufacturing facility, where we isolate the T cells and genetically engineer them using TCR sequences from the ImmunoBank.

We believe the continued expansion and diversification of the ImmunoBank will enable us to deliver customized multiplexed TCR-T therapy to patients, where each patient’s T cells are engineered with multiple TCRs that are matched to their specific tumor and HLA type.

For example, if a patient’s tumor expresses high levels of a particular cancer target, their T cells will be reprogrammed with a TCR that recognizes that particular cancer target.

The FDA's clearance of our T-Plex IND for the simultaneous combination of different TCRs, as well as secondary INDs for the first two TCRs in our solid tumor program, allows us to rapidly and efficiently expand the ImmunoBank and enables us to work toward our goal of bringing customized, multiplexed therapies to patients.

Once the T cells are engineered with a combination of the most relevant TCRs, they will be transported back to the hospital and reintroduced into the patient by intravenous infusion.

Following the infusion, the engineered T cells, which are designed to recognize multiple targets expressed by the patient’s tumor, will proliferate in vivo and mount an anti-cancer immune response.

Following the infusion, the engineered T cells, which are designed to recognize

multiple targets expressed by the patient’s tumor, will proliferate in vivo and mount an anti-cancer immune response.

Our patient treatment and manufacturing process is summarized in the graphic below.

7 unchanged sentences

Our TCR-T therapies are designed to be used in combination with each other.

We believe this approach may allow us to overcome the limitations and challenges of TCR-T therapy development to date.

As the ImmunoBank is populated with more TCRs, we expect that patient eligibility will expand, as will our target market opportunities.

Our approach is expandable.

ImmunoBank has the flexibility to be used with new and optimized methods of T cell engineering that we may develop over time.

The ImmunoBank has the flexibility to be used with new and optimized methods of T cell engineering that we may develop over time.

Our proprietary platform is designed to:

5 unchanged sentences

The central elements of our platform that differentiate us from other cell therapy companies are our proprietary platform technologies:

TargetScan, ReceptorScan, SafetyScan, ImmunoBank and T-Integrate.

TargetScan, ReceptorScan, SafetyScan, the ImmunoBank and T-Integrate.

TargetScan—Identification of Novel Targets of Clinically Active TCRs

2 unchanged sentences

It can be applied to virtually any TCR that plays a role in the cause or prevention of disease.

To identify the target of a clinically active TCR found in the T cells of a patient actively responding to immunotherapy, we mix T cells expressing that TCR with a genome-wide library of target cells where every cell in the library expresses a different protein fragment.

To identify the target of a clinically active TCR found in the T cells of a patient responding to immunotherapy, we mix T cells expressing that TCR with a genome-wide library of target cells where every cell in the library expresses a different protein fragment.

In each target cell, the protein fragment is processed naturally by the proteasome or immunoproteasome and the resulting peptides are displayed on cell-surface MHC proteins.

9 unchanged sentences

common oncogenic driver mutations, cancer/testis antigens, human endogenous retroviruses, or HERVs, and a large collection of sequences that are not translated in normal tissue but frequently translated in human cancers.

We constructed our libraries using a tiling pattern of overlapping fragments to provide complete and redundant coverage of every targeted sequence, as shown in the graphic below.

Oncology Target Discovery Library (Version 3.0)

Our Oncology Target Discovery Library allows us to precisely identify the novel targets recognized by TCRs from patients who are actively responding to immunotherapy.

In addition, because the library comprehensively covers every non-mutated human protein sequence, we are also able to fully characterize all potential off-target interactions for any given TCR, which we believe will help us reduce the risk and enhance the potential safety profile of our TCR-T therapy candidates before we advance them to clinical development.

We constructed our libraries using a tiling pattern of overlapping fragments to provide complete and redundant coverage of every targeted sequence.

Our Oncology Target Discovery Library allows us to precisely identify the novel targets recognized by TCRs from patients who are responding to immunotherapy.

risk and enhance the potential safety profile of our TCR-T therapy candidates before we advance them to clinical development.

Furthermore, we can use our screen for any HLA type, enabling target discovery across a wide range of patient demographics.

To validate our TargetScan technology, we performed the following proof-of-concept screens using our Oncology Target Discovery Library (version 2.0), which includes approximately 600,000 protein fragments spanning every human protein.

In the first screen, we used a naturally occurring TCR that is known to recognize the protein MAGE-A3.

As shown below, our screen correctly identified the primary target of this TCR, and also identified three off-targets, including two that are unrelated at the gene level to MAGE-A3 and would likely not have been identified in a bioinformatic search.

TargetScan Proof-of-Concept:

Target Screen of MAGE-A3 Specific TCR Identifies MAGE-A3 and Three Off-Target

SafetyScan—Elimination of Off-Target Activity

2 unchanged sentences

The ability to identify problematic off-targets is critical as TCR-T therapies engineered with TCRs that recognize off-targets expressed at high levels in critical organs could cause toxicities, thereby limiting their therapeutic potential.

To further validate this application of our technology, we used SafetyScan to screen an affinity-enhanced version of the MAGE-A3 TCR described above.

We use SafetyScan to screen affinity-enhanced versions of TCRs.

Affinity enhancement is a process by which a naturally occurring TCR is mutated in order to generate a more potent therapeutic construct.

The affinity-enhanced TCR that we screened had previously entered clinical trials with a different sponsor, but human testing of the TCR was halted abruptly because two patients treated with T cells engineered to express this affinity-enhanced TCR died of acute cardiac failure within five days of T cell administration.

One such affinity-enhanced TCR that we screened had previously entered clinical trials with a different sponsor, but human testing of the TCR was halted abruptly because two patients treated with T cells engineered to express this affinity-enhanced TCR died of acute cardiac failure within five days of T cell administration.

Subsequent studies revealed that this TCR recognized an off-target derived from the muscle protein Titin, which is abundantly expressed in cardiac tissue.

When we screened this same affinity-enhanced TCR using our SafetyScan technology, we identified a variety of potential additional off-targets which were not seen in our screen of the natural TCR, including the protein Titin, as shown below.

This experiment demonstrates why we believe that our SafetyScan technology provides a significant competitive advantage, because it enables us to rapidly and efficiently eliminate from our preclinical pipeline TCRs that are identified as recognizing potentially problematic off-targets.

1 unchanged sentence

We believe that SafetyScan thereby has the potential to enable us to decrease the risk of encountering unexpected toxicities in our clinical trials by providing a genome-wide understanding of off-target effects.

SafetyScan Proof-of-Concept:

Target Screen of Affinity-Enhanced MAGE-A3-Specific TCR Identifies Clinically Relevant Off-target Linked to Toxicity

Using TargetScan, we have identified more than 60 shared antigens in patient tumors, and over 90% of these targets have not previously been identified as targets for TCR-T therapy.

Using our TargetScan technology, we have identified about 100 novel antigens as targets of tumor infiltrating T cells from patients who are responding to immunotherapy.

3 unchanged sentences

To enable the rapid, cost-effective, and consistent manufacturing of TCRs, we have developed a non-viral vector delivery system that we refer to as T-Integrate.

Our manufacturing platform enables us to introduce any of the TCRs from ImmunoBank, along with additional genetic elements such as CD8 that further augment T cell function, into the genomes of patient- or donor-derived T cells.

Our manufacturing platform enables us to introduce any of the TCRs from the ImmunoBank, along with additional genetic elements such as CD8 that further augment T cell function, into the genomes of patient- or donor-derived T cells.

Genetically engineering a T cell requires two steps:

10 unchanged sentences

As of February 28, 2023, we have successfully manufactured TSC-100 and TSC-101 but have not yet dosed patients in our hematological malignancies program.

The FDA has cleared three INDs for our solid tumor program, including our primary IND, T-Plex which supports the simultaneous use of multiple TCRs to create customized, multiplexed TCR-T cell therapy candidates, as well as INDs for TSC-204-A0201 and TSC-204-C0702.

Our T-Integrate Manufacturing Platform

10 unchanged sentences

This tag does not interfere with the function of CD8 alpha but provides a way to easily purify the engineered T cells during our manufacturing process.

We plan to further enhance our T cell therapies with the addition of a TGFβ

blocker to overcome the immunosuppressive tumor microenvironment.

We plan to further enhance our T cell therapies with the addition of DN-TGFβRII to overcome the immunosuppressive tumor microenvironment.

An illustration of the construct of our TCR-T therapies is shown below.

3 unchanged sentences

With our differentiated platform as our foundation, we are building a three-pillar research and development strategy to create transformational TCR-T therapies for patients, as shown below.

Our Liquid Tumor Program

We are developing our liquid tumor program to treat patients with hematologic malignancies who are undergoing allogeneic HCT.

Our Hematologic Malignancies Program

We are developing our hematologic malignancies program to treat patients with non-B cell malignancies (AML, MDS, ALL) who are undergoing allogeneic HCT.

In the first phase of our clinical development strategy, we are initially focusing on well-recognized cancer targets that have been discovered in patients with exceptional responses to HCT-associated immunotherapy, including HA-1 and HA-2.

7 unchanged sentences

This strategy therefore enables high levels of anti-cancer efficacy with what we believe to be less risk of life-threatening toxicities to normal cells.

We plan to conduct clinical trials of our lead TCR-T therapy candidates, TSC-100 and TSC-101, in parallel, with patients enrolled in treatment arms based on their genotype, as shown below.

We are conducting clinical trials of our lead TCR-T therapy candidates, TSC-100 and TSC-101, in parallel, with patients to be enrolled in treatment arms based on their genotype, as shown below.

Patients who are positive for the target antigen, HA-1 or HA-2, as well as the HLA-A*02:01 allele, which is the HLA type required to display HA-1 and HA-2 on the cell surface for recognition by a T cell, will be eligible for enrollment.

2 unchanged sentences

Background on Hematologic Malignancies

Hematopoietic stem cell transplantation, or HCT, has become the standard of care for many hematologic malignancies.

HCT has become the standard of care for many hematologic malignancies.

When a patient with leukemia undergoes HCT, they start by receiving a conditioning regimen of high dose chemotherapy with or without radiation.

2 unchanged sentences

The stem cells engraft in their bone marrow and start to repopulate their body with new blood cells, which are now genetically identical to the donor.

HCT has demonstrated the rare opportunity in cancer treatment to generate long-term remissions or cures.

HCT has demonstrated the rare

opportunity in cancer treatment to generate long-term remissions or cures.

For example, patients with acute myeloid leukemia, or AML, who receive HCT have a five-year post-transplant survival rate of 44%.

15 unchanged sentences

host disease, or GvHD, but if the miHAs are only expressed in blood cells, a specific GvL effect is observed without an increase in GvHD.

Our liquid tumor program is focused on targeting miHAs that are exclusively expressed in hematopoietic cells in order to induce the GvL effect while potentially mitigating the risk of GvHD.

TSC-100 is an allogeneic TCR-T therapy candidate directed at eliminating all native blood cells, including residual cancer cells, in HA-1-positive and HLA-A*02:01-positive patients with hematologic malignancies who undergo HCT using a donor who is either HA-1-negative or HLA-A*02:01-negative.

Our hematologic malignancies program is focused on targeting miHAs that are exclusively expressed in hematopoietic cells in order to induce the GvL effect while potentially mitigating the risk of GvHD.

HA-1-negative or HLA-A*02:01-negative.

Using ReceptorScan, we screened over a hundred million CD8+ T cells and identified and assessed hundreds of highly active TCRs that recognize the HA-1 antigen.

2 unchanged sentences

We believe that donor T cells specifically engineered to express TCR-100a will generate an anti-tumor effect in patients, leading to a reduction in relapse rates and an increase in long-term survival.

In the fourth quarter of 2021, we filed an IND for TSC-100 with the FDA.

The FDA cleared our IND for TSC-100, enabling us to move forward with Phase 1 clinical development.

HA-1 was one of the first miHAs to be discovered in a patient undergoing HCT.

10 unchanged sentences

In parallel, T cells isolated from the same donor will be genetically engineered to recognize HA-1.

Once engraftment of donor stem cells is established in the patient, TSC-100 will be infused

into the patient with the goal of eliciting a highly specific anti-tumor effect.

Once engraftment of donor stem cells is established in the patient, TSC-100 will be infused into the patient with the goal of eliciting a highly specific anti-tumor effect.

The engineered donor T cells are designed to recognize and eliminate all of the patient’s native blood cells, including residual leukemia cells, which are HA-1-positive, thereby preventing relapse and potentially promoting complete cures.

2 unchanged sentences

TSC-100 Treatment Paradigm

Preclinical Data

Using ReceptorScan, we screened over 175 million T cells from six healthy donors to identify naturally occurring TCRs specific for HA-1.

We then extensively characterized over 300 of these TCRs for their ability to specifically recognize and kill tumor cells that express HA-1.

We prioritized TCRs with the highest potency in cytotoxicity assays and in their production of cytokines associated with increased T-cell activation and function.

Through this screening process, we identified TCR-100a, which exhibited superior potency compared to the other TCRs.

We assessed the in vitro HA-1-specific cytotoxicity of TCR-100a using cell lines with various levels of HA-1 expression, as shown below.

THP1, a cell line that expresses moderate levels of HA-1, was susceptible to cell killing by multiple TCRs we tested.

However, TF1, a cell line that expresses less than half the level of HA-1 expressed by THP1, was sensitive to cell killing by TCR-100a but was resistant to almost all other HA-1-specific TCRs, including TCRs reported in the literature.

Our preclinical studies also demonstrated that SUDHL1 cells, which lack HA-1 expression, were resistant to all tested HA-1-specific TCRs, as expected, highlighting the high selectivity and potential safety of TCR-T therapies.

In Vitro Studies Demonstrate Superior HA-1-Specific Cytotoxicity

of TCR-100a Compared to Other TCRs

Because people inherit two copies of every chromosome, one from their mother and one from their father, everyone has two copies of the ARHGAP45 gene.

1 unchanged sentence

To ensure that TSC-100 is able to effectively eliminate healthy blood cells and leukemia cells that are either homozygous HA-1-positive (+/+) or heterozygous HA-1-positive (+/-), we assessed the activity of TSC-100 against blood cells derived from a variety of healthy donors and patients with AML and ALL.

As shown below, TSC-100 eliminates both homozygous and heterozygous HA-1-positive healthy blood cells and leukemia cells.

TSC-100 Displays Specific Cytotoxic Activity Towards HA-1-positive Cells

In preclinical studies, TSC-100 eliminated both homozygous and heterozygous HA-1-positive healthy blood cells and leukemia cells.

It is known in the cell therapy field that TCRs which exhibit off-target effects can potentially cause toxicity.

In order to reduce the potential for TCR-100a to exhibit problematic off-target effects, we used SafetyScan to comprehensively scan for any other potential targets recognized by TCR-100a.

This screen was performed using a subset of our Oncology Target Discovery Library (version 2.0), which includes approximately 600,000 protein fragments and collectively spans every protein encoded in the human proteome as well as all common SNPs.

As shown below, all three protein fragments in the library that contain the HA-1-positive peptide antigen were strongly enriched in the screen, and no significant off-target interactions were observed.

In the screen, all three protein fragments in the library that contain the HA-1-positive peptide antigen were strongly enriched, and no significant off-target interactions were observed.

In contrast, some of the other HA-1-specific TCRs identified by ReceptorScan did exhibit off-target effects, highlighting our ability to select candidates that we believe have favorable risk/benefit profiles.

SafetyScan Screen Reveals No Significant Off-Targets for TCR-100a

To further evaluate the potential safety profile of TSC-100, we screened TCR-100a against HA-1-positive and HA-1-negative cells that individually express each of the 108 most common HLA alleles.

In the HA-1-positive cells, TCR-100a was able to mediate efficient recognition in cells expressing HLA-A*02:01 as well as in cells expressing two related HLA types, HLA-A*02:02 and HLA-A*02:06.

This suggests that patients with any of these three HLA types could potentially benefit from TSC-100.

Notably, TCR-100a showed no recognition of HA-1-negative cells across all 108 HLA types, indicating low risk of alloreactivity or misrecognizing other antigens on other HLA types, as shown below.

TSC-100 Shows No Detectable Alloreactivity Across 108 Different HLA Types

Similar to TSC-100, TSC-101 is an allogeneic TCR-T therapy candidate directed at eliminating residual cancer cells in HA-2-positive and HLA-A*02:01-positive patients with hematologic malignancies who undergo HCT using a donor who is either HA-2-negative or HLA-A*02:01-negative.

3 unchanged sentences

In the fourth quarter of 2021, we filed an IND for TSC-101.

The FDA placed a clinical hold on the TSC-101 IND;

we received written communication from the FDA asking for additional assessment of the potential for off-tumor reactivity in certain tissues and are working with the agency to resolve its questions as quickly as possible.

The FDA cleared our IND for TSC-101, enabling us to move forward with Phase 1 clinical development.

Unlike HA-1, the HA-2 antigen is highly prevalent, with approximately 95% of individuals in the United States being HA-2-positive.

However, as with HA-1, a specific HLA type, HLA-A*02:01, which is present in approximately 42% of individuals in the United States, is required to display the HA-2 antigen on the cell surface for recognition by a T cell.

As a result, approximately 40% of

HCT patients would be positive for both HA-2 and HLA-A*02:01 and therefore be eligible for treatment with TSC-101 using a donor who is negative for HLA-A*02:01, regardless of whether the donor is HA-2-positive or HA-2-negative.

As a result, approximately 40% of HCT patients would be positive for both HA-2 and HLA-A*02:01 and therefore be eligible for treatment with TSC-101 using a donor who is negative for HLA-A*02:01, regardless of whether the donor is HA-2-positive or HA-2-negative.

Such donors are straightforward to identify and should be available to most patients who undergo half-matched, or haploidentical, transplantation using family members as donors, as patients typically have between two and three potential haploidentical donors.

Preclinical Data

Similar to TCR 100a, we used ReceptorScan to identify TCR 101a.

5 unchanged sentences

The discovery of TCR-101 was presented at the 63 rd American Society of Hematology Annual Meeting and Exposition, in December 2021.

TCR-101a Demonstrates High Activity Similar to TSC100a

Clinical Development Plan for Our Liquid Tumor Program

Clinical Development Plan for Our Hematologic Malignancies Program

Background on Types of HCT

7 unchanged sentences

Donors who are siblings of the patient and are perfectly matched for eight out of eight HLA alleles are considered the highest priority donor type for patients undergoing allogeneic HCT, but these types of donors are available for less than a third of patients.

For the majority of patients, the choice is between an unrelated donor who is perfectly matched for eight out of eight HLA alleles, referred to as a matched unrelated donor, or MUD, or a

family member such as a sibling, parent or child who has a half-match with the patient, referred to as a haploidentical donor, or haplo.

For the majority of patients, the choice is between an unrelated donor who is perfectly matched for eight out of eight HLA alleles, referred to as a matched unrelated donor, or MUD, or a family member such as a sibling, parent or child who has a half-match with the patient, referred to as a haploidentical donor, or haplo.

Historically, haplo donor transplantation was associated with much higher GvHD than MUD-transplants, but a recent treatment regimen that uses chemotherapy given three days after stem cell infusion called post-transplantation cyclophosphamide, or PTCy, specifically kills immune cells that cause GvHD.

4 unchanged sentences

Because the patient’s new healthy blood cells are derived from the donor and are therefore either target-negative or not able to express the target, we believe TSC-100 and TSC-101 should have minimal toxic side effects.

Planned Phase 1 Clinical Trial

We are planning to conduct clinical studies for TSC-100 and TSC-101 within a multi-arm, controlled, Phase 1, ‘umbrella’

Phase 1 Clinical Trial

We have initiated clinical studies for TSC-100 and TSC-101 within a multi-arm, controlled, Phase 1, ‘umbrella’

design clinical trial to investigate the safety and efficacy of TSC-100 and TSC-101 in patients with ALL, AML, and MDS, that are undergoing HCT following RIC.

Our Phase 1 clinical trial is designed to include measurements of early surrogate markers of efficacy, such as chimerism, or the percentage of blood cells that are donor-derived, and whether patients continue to have detectable residual leukemia in their post-transplant bone marrow biopsy, both of which are predictors of relapse.

As shown in the graphic below, we also plan to include a control arm, comprising patients who do not meet the HLA or miHA genetic criteria and are treated with standard RIC haplo transplantation alone.

As shown in the graphic below, we are also including a control arm, comprising patients who do not meet the HLA or miHA genetic criteria and are treated with standard RIC haplo transplantation alone.

Comparisons of both safety and efficacy outcomes with this control arm will potentially enable all patients treated with TSC-100 or TSC-101 to be included as part of the efficacy analysis for the initial Phase 1 trial prior to transitioning the program into a registrational Phase 2 trial towards a future biologics license application, or BLA, filing.

Planned Multi-Arm Phase 1 Clinical Trial Design

Multi-Arm Phase 1 Clinical Trial Design

Anticipated timeline

We filed INDs on TSC-100 and TSC-101 in the fourth quarter of 2021.

The FDA has cleared our IND for TSC-100, enabling us to move forward with our clinical development plan for TSC-100.

We anticipate dosing the first patient in the TSC-100 arm of our Phase 1 clinical trial in the first half of 2022;

and presenting initial clinical data on our Phase 1 trial in the second half of 2022.

The FDA placed a clinical hold on our IND for TSC-101.

We received written communication from the FDA asking for additional assessment of the potential for off-tumor reactivity in certain tissues and are working with the agency to resolve its questions as quickly as possible.

We filed INDs for TSC-100 and TSC-101 in the fourth quarter of 2021.

The FDA has cleared our INDs for TSC-100 and TSC-101, enabling us to move forward with our clinical development plans.

We expect to enroll patients in all three arms in the Phase 1 umbrella trial for TSC-100 and TSC-101 and plan to report safety and biomarker data mid-year.

Additionally, we expect that we will reach the recommended Phase 2 dose for TSC-100 and TSC-101 and report further clinical safety and biomarker data for the program by the end of 2023.

We expect to report prevention of relapse data in 2024.

Future market expansion opportunities

If TSC-100 and TSC-101 demonstrate the ability to significantly reduce relapse rates after hematopoietic cell transplantation, there could potentially be new opportunities to expand the curative potential of HCT combined with TSC products to greater numbers of patients.

If TSC-100 and TSC-101 demonstrate the ability to significantly reduce relapse rates after HCT, there could potentially be new opportunities to expand the curative potential of HCT combined with TSC products to greater numbers of patients.

Currently, only about 7,000 patients undergo HCT per year in the United States out of approximately 40,000 patients diagnosed each year with AML, MDS and ALL.

7 unchanged sentences

If successful, this would further expand the curative potential of HCT combined with TSC therapy to older, frailer patients.

A final market expansion opportunity could occur from the use of TSC products as a chemotherapy andradiation free conditioning regimen for non-malignant diseases such as sickle cell anemia which are currently treated with HCT.

A final market expansion opportunity could occur from the use of TSC products as a chemotherapy and radiation-free conditioning regimen for non-malignant diseases such as sickle cell anemia which are currently treated with HCT.

Since chemotherapy and radiation are associated with the risk of long-term toxicities such as cancer, heart damage, lung damage and infertility, cellular therapies such as TSC-100 or TSC-101 could reduce those risks and increase the numbers of patients willing to undergo HCT.

5 unchanged sentences

Our first five solid tumor TCR-T therapy candidates include a combination of known targets, such as HPV16 for TSC-200, PRAME for TSC-203, and MAGE-A1 for TSC-204, as well as novel TCR-T therapy targets that have not yet been tested in the clinic, such as TSC-201 and TSC-202.

We are currently advancing our five solid tumor TCR-T therapy candidates through lead optimization, and we expect to submit IND applications for two candidates in the second half of 2022, with additional IND submissions expected to be filed in 2023.

In addition to our five lead solid tumor TCR-T therapy candidates, we have identified over 60 novel antigens based on tumor samples from patients who are actively responding to immunotherapy using our TargetScan technology.

Our six solid tumor TCR-T therapy candidates include a combination of known targets, such as HPV16 for TSC-200, PRAME for TSC-203, and MAGE-A1 for TSC-204, as well as novel TCR-T therapy targets that have not yet been tested in the clinic, such as TSC-201, TSC-202, and TSC-205.

We are currently advancing our six solid tumor TCR-T therapy candidates.

We received FDA clearance for our initial three INDs for the treatment of solid tumors.

These include a primary IND for the entire solid tumor program, which we refer to as T-Plex, which supports the simultaneous use of multiple TCRs to create customized, multiplexed TCR-T cell therapy candidates based on target and HLA expression.

The FDA also cleared INDs for TSC-204-A0201 and TSC-204-C0702, the first two TCRs in the ImmunoBank, targeting MAGE-A1 on HLA types A*02:01 and C*07:02, respectively.

We plan to further expand the ImmunoBank by filing INDs for additional TCRs throughout 2023.

In addition to our six lead solid tumor TCR-T therapy candidates, we have identified about 100 novel antigens as targets of tumor infiltrating T cells from patients who are responding to immunotherapy using our TargetScan technology.

We are in early stages of analyzing these additional novel antigens and plan to advance those that we believe have the best potential as a TCR-T therapy candidate into preclinical development.

We are building ImmunoBank, a collection of highly active TCRs, to enable multiplexed TCR-T therapy.

Our vision is to expand ImmunoBank with TCRs that recognize diverse targets and are associated with multiple HLA types in order to provide a broad array of therapeutic options for patients with various types of solid tumors.

We are building the ImmunoBank, a collection of highly active TCRs, to enable multiplexed TCR-T therapy.

Our vision is to expand the ImmunoBank with TCRs that recognize diverse targets and are associated with multiple HLA types in order to provide a broad array of therapeutic options for patients with various types of solid tumors.

For patients with a solid tumor malignancy, we plan to analyze their tumor to determine which targets are expressed at high levels in their particular cancer.

We will then access ImmunoBank and select up to three TCRs that match their HLA type and address the most highly expressed targets in their tumor.

We will then access the ImmunoBank and select up to three TCRs that match their HLA type and address the most highly expressed targets in their tumor.

We will use this set of TCRs to genetically reprogram their T cells to recognize these targets and the resulting engineered T cells will be infused back into the patient as a multiplexed TCR-T therapy.

16 unchanged sentences

We are using ReceptorScan to discover highly active TCRs for these previously identified targets to complement the discovery of our novel TCR/target pairs.

Finally, ImmunoBank will allow us to target multiple HLA types to prevent target loss and increase durability of response.

Finally, the ImmunoBank will allow us to target multiple HLA types to prevent target loss and increase durability of response.

Novel Targets Identified from Patients with Head and Neck Cancer

4 unchanged sentences

As an example, if a particular TCR sequence is observed at 0.05% frequency in the tumor before the patient receives immunotherapy and then increases to 5% after the tumor starts to shrink, the T cell has clonally expanded 100-fold and is likely to have played a causal role in driving the patient’s clinical response.

Certain TCR sequences are not detectable in the pre-treatment biopsy but are observed at high frequency in the post-treatment tumor.

Certain TCR sequences are not detectable in the pre-treatment biopsy but

are observed at high frequency in the post-treatment tumor.

These emerging clones are also potential candidates for driving the patient’s clinical response.

1 unchanged sentence

Clinically Relevant Anti-Cancer T Cells Identified Through T Cell Sequencing

We have performed genome-wide TargetScan screens on over 100 TCRs derived from T cells that clonally expanded in the tumors of patients with head and neck cancer who are responding to immune checkpoint inhibitors, which has resulted in our discovery of over 60 novel shared antigens.

An example of one such screen is shown below.

This screen was performed with our Oncology Target Discovery Library (version 2.0), which comprises over 600,000 protein fragments.

Two protein fragments, shown in dark pink, were specifically recognized by the TCR.

Due to the redundancy built into our library through its overlapping tiling pattern, both of the identified clones contain the same nine amino acid-long peptide antigen that we determined to be the target of this TCR.

Notably, no off-targets were observed in the screen, highlighting the value of the SafetyScan technology in identifying TCRs with clean specificity profiles.

Identification of a Novel Target from a Patient with Head and Neck Cancer

Novel Targets Identified from Patients with Melanoma

9 unchanged sentences

Because this library is substantially less complex than our genome-wide Oncology Target Discovery Library, we can screen the TargetScan library with dozens of TCRs simultaneously.

For example, the screen shown below was conducted with 35 TCRs derived from 11 patients with melanoma who received TIL therapy.

For example, we screened 35 TCRs derived from 11 patients with melanoma who received TIL therapy.

In a single screen, we identified three TCR/target pairs that recognize CTAs, including the antigen target for one of our lead solid tumor product candidates, TSC-201, which we refer to as Target-201, as well as two other antigens that have not previously been identified as targets for TCR-T therapy.

Three Novel Cancer/Testis Antigen Targets Identified

from TIL-Responsive Patients

TCR and Target Validation Process

When we discover novel TCR/target pairs, we first determine if the gene that encodes the target is expressed at high levels in normal tissue.

As shown below, Target-201 is exclusively expressed in testis, which is an immune privileged tissue and, as a result, should not pose a significant safety concern.

We also examine how frequently the target is expressed in various solid tumors.

As shown below in dark pink, Target-201 is overexpressed in a high percentage of melanoma tumor samples as well as in several other tumor types, including non-small cell lung cancer, or NSCLC, head and neck cancer, and cervical cancer.

Selective Expression of Target-201 in Multiple Tumor Types vs.

Normal Tissues

We found that Target-201 is exclusively expressed in testis, which is an immune privileged tissue and, as a result, should not pose a significant safety concern.

We also examined how frequently the target is expressed in various solid tumors.

In the screen, Target-201 was overexpressed in a high percentage of melanoma tumor samples as well as in several other tumor types, including non-small cell lung cancer, or NSCLC, head and neck cancer, and cervical cancer.

Next, as part of our discovery process, we test if the TCRs discovered with our approach are able to kill cancer cells that naturally express the relevant target and specific HLA type.

2 unchanged sentences

Finally, to reduce the risk that a TCR discovered in a targeted screen recognizes any problematic off-targets, we re-screen the TCR using SafetyScan and our genome-wide library.

As shown below, when the TCR that recognizes Target-201 was re-screened using our Oncology Target Discovery Library (version 2.0), which includes protein fragments spanning every normal protein encoded in the human genome, only one potential off-target was observed.

When the TCR that recognizes Target-201 was re-screened using our Oncology Target Discovery Library, which includes protein fragments spanning every normal protein encoded in the human genome, only one potential off-target was observed.

We subsequently identified several cell lines that naturally express the full-length protein from which the off-target antigen was derived and found that T cells engineered with the TCR do not recognize or kill these cells.

1 unchanged sentence

This shows that our genome-wide screen detects potential off-targets with very high sensitivity, and that not all off-targets detected in this manner are problematic.

In the event, however, that a TCR exhibits

problematic off-target effects, we can use ReceptorScan to discover alternative TCRs that have similar anti-cancer effects but do not cross-react with proteins expressed at high levels on normal tissue or critical organs.

Genome-Wide Safety Screen of Target-201 TCR Using SafetyScan

In the event, however, that a TCR exhibits problematic off-target effects, we can use ReceptorScan to discover alternative TCRs that have similar anti-cancer effects but do not cross-react with proteins expressed at high levels on normal tissue or critical organs.

To further expand the pool of addressable patients with our TSC-200 series of product candidates, we can also use ReceptorScan to identify TCRs recognizing antigens on the same target protein that are presented by different HLA alleles.

2 unchanged sentences

TSC-200 Series

Our first five solid tumor TCR-T therapy candidates include a combination of known targets, such as HPV16 for TSC-200, PRAME for TSC-203, and MAGE-A1 for TSC-204, as well as targets that are novel antigens for TCR-T therapy, such as for TSC-201 and TSC-202.

Our six solid tumor TCR-T therapy candidates include a combination of known targets, such as HPV16 for TSC-200, PRAME for TSC-203, and MAGE-A1 for TSC-204, as well as targets that are novel antigens for TCR-T therapy, such as for TSC-201, TSC-202, and TSC-205.

All of these targets are frequently expressed in the solid tumors of interest to us, including melanoma, head and neck cancer, NSCLC, and cervical cancer.

3 unchanged sentences

In parallel with our TargetScan discovery efforts in head and neck cancer, we are using ReceptorScan to discover highly active TCRs that target antigens in human papilloma virus, or HPV, for our TSC-200 program.

Over 25% of head and neck cancers are caused by HPV infection, including up to 70% of oropharangeal cancers.

Over 25% of head and neck cancers are caused

by HPV infection, including up to 70% of oropharangeal cancers.

HPV antigens are a particularly compelling set of targets due to the fact that HPV proteins drive tumorigenesis in these cancers, which means that these proteins are (1) present in every tumor cell in an HPV-positive tumor and (2) essential to the survival of the tumor cell.

25 unchanged sentences

Using ReceptorScan, we have identified thousands of TCRs across multiple PRAME-derived epitopes presented on HLA-A*02:01, and we are currently identifying the most active TCR to advance to IND-enabling studies.

In addition, we are using TargetScan on clinically active TCRs from patients with melanoma and head & neck cancer to identify novel PRAME epitopes presented on other HLA types.

In addition to our five lead solid tumor TCR-T therapy candidates, we have identified more than 60 novel antigens using TargetScan, of which over 90% have not previously been publicly disclosed as targets for TCR-T therapy.

Although target validation naturally results in attrition, it is clear that tumor-resident T cells recognize many more shared antigens than have been reported to date.

Many of the antigens we have identified are expressed across multiple solid tumor types and some have expression levels comparable or superior to targets currently in clinical development by others such as NY-ESO-1.

We are currently in the process of validating several of these additional novel antigens and identifying potential TCR/target pairs using our platform technologies.

We plan to continuously expand ImmunoBank with TCRs for both known and novel targets as well as address different HLA types to enable customized multiplexed TCR-T therapy while also addressing the potential issue of HLA loss leading to resistance for a wide range of solid tumor patients.

We are developing TSC-204 as a TCR-T therapy candidate targeting a known cancer antigen, m elanoma-associated antigen 1 , or MAGE-A1, that will include multiple TCRs for different HLA-restricted epitopes on this target.

In addition, we are using TargetScan on clinically active TCRs from patients with melanoma and head and neck cancer to identify novel PRAME epitopes presented on other HLA types.

We are developing TSC-204 as a TCR-T therapy candidate targeting a known cancer antigen, melanoma-associated antigen 1, or MAGE-A1, that will include multiple TCRs for different HLA-restricted epitopes on this target.

Using our TargetScan platform we have identified MAGE-A1 as one of the targets of T cells from a head and neck cancer patient responding to checkpoint inhibitor therapy.

From this patient, we discovered multiple different TCRs recognizing a novel HLA-C*07:02 restricted epitope of MAGE-A1 which is a cancer/testis gene frequently overexpressed in a wide variety of solid tumors, including approximately 45% of head & neck cancers, 50% of melanomas, 50% of cervical cancers and 50% of non-small cell lung cancers.

From this patient, we discovered multiple different TCRs recognizing a novel HLA-C*07:02 restricted epitope of MAGE-A1 which is a cancer/testis gene frequently overexpressed in a wide variety of solid tumors, including approximately 45% of head and neck cancers, 50% of melanomas, 50% of cervical cancers and 50% of non-small cell lung cancers.

In addition to these highly active HLA-C*07:02 restricted TCRs, we are also using ReceptorScan to identify additional clinical TCRs for MAGE-A1 epitopes presented on multiple

1 unchanged sentence

TScan believes that it is the only company with a disclosed TCR program in MAGE-A1 for HLA types other than A*02:01.

The Company anticipates filing an IND for TSC-204 in the second half of 2022.

The Company filed INDs for TSC-204-A0201 and TSC-204-C0702 in December 2022, and the FDA cleared these INDs in January 2023, allowing us to proceed with Phase 1 clinical development enabling activities.

We are developing TSC-205, a known cancer antigen, as a TCR-T therapy candidate.

Expression of this antigen is distinct from our current clinical targets, with especially prevalent expression in head and neck and non-small cell lung cancers.

Using our ReceptorScan platform, we have generated candidate TCRs for two different epitopes derived from TSC-205.

Although target validation naturally results in attrition, it is clear that tumor-resident T cells recognize many more shared antigens than have been reported to date.

We are currently in the process of validating several of these additional novel antigens and identifying potential TCR/target pairs using our platform technologies.

We plan to continuously expand the ImmunoBank with TCRs for both known and novel targets as well as address different HLA types to enable customized multiplexed TCR-T therapy candidates while also addressing the potential issue of HLA loss leading to resistance for a wide range of solid tumor patients.

Clinical Development Plan for Our Solid Tumor Program

For the initial first-in-human studies for our TSC-200 series of TCR-T therapy candidates, we plan to evaluate multiple TCRs in parallel to determine the safety and preliminary efficacy of multiplexed TCR-T therapy.

We envision using TSC-200 as the backbone therapy for patients with HPV-positive malignancies, including head and neck, cervical, and anal cancers.

In January 2023, the FDA cleared our IND application for T-Plex, which will serve as the primary IND for our solid tumor program, enabling customized combinations of TCR-Ts to be administered to patients based on the targets and HLAs expressed in their tumors.

Specific TCRs for each patient will be chosen from the ImmunoBank consisting of high affinity, naturally occurring TCRs that recognize a variety of prevalent cancer-specific targets and are associated with common HLA types.

Each unique TCR-T will be filed as a secondary IND and will reference the primary T-Plex IND.

In addition to the T-Plex IND, the FDA cleared secondary INDs for two initial TCR-T product candidates, TSC-204-A0201 and TSC-204-C0702, targeting melanoma associated antigen 1 (MAGE-A1) on HLA types A*02:01 and C*07:02.

MAGE-A1 is a cancer-associated antigen overexpressed in 45% of head and neck cancers and 50% of melanoma, cervical, and non-small cell lung cancers.

We believe that TSC-204-C0702 is the first clinical program in MAGE-A1 for an HLA type other than A*0201.

We are now conducting activities to enable the initiation of a multicenter Phase 1 clinical trial to evaluate the safety, preliminary efficacy, and feasibility of repeat dosing of multiplexed TCR-T therapy.

We plan to enroll patients with non-small cell lung cancer, melanoma, head and neck cancer, ovarian, and cervical cancer.

We expect that many of the clinical trial sites enrolling patients in our hematologic malignancies program are planning to join our solid tumor Phase 1 study.

We plan to begin enrolling patients in the screening protocol of this study by the middle of this year, with patient dosing expected to commence in the third quarter of 2023.

We plan to share initial safety and biomarker data for the most advanced single-agent TCRs by the end of 2023, with initial multiplex therapy data for our first combination of TCRs under T-Plex expected in the first half of 2024.

We plan to further populate the ImmunoBank with additional targets and HLA types, including cancer/testis antigens and TCRs targeted at epitopes of HPV.

We envision these HPV-targeting TCRs will serve as a backbone therapy for patients with HPV-positive malignancies, including head and neck, cervical, and anal cancers.

According to the Centers for Disease Control, the incidence of HPV-positive cancers in the U.S.

is approximately 46,000 cases per year, with five-year survival rates ranging from approximately 50% to 70%.

The targets of TSC-201, TSC-202, TSC-203, and TSC-204 are also frequently expressed in the solid tumors of interest to us, as shown below.

The targets of TSC-201, TSC-202, TSC-203, TSC-204, and TSC-205 are also frequently expressed in the solid tumors of interest to us, as shown below.

Cancer Expression Levels for the Targets of our Lead Solid Tumor Programs

After establishing single agent safety for each of our initial solid tumor TCR-T therapy candidates in a multi-arm Phase 1 clinical trial, we plan to test TSC-200 in combination with TSC-201, TSC-202, or TSC-203 in patients who are positive for the respective targets of these therapies.

After establishing single agent safety for each of our initial solid tumor TCR-T therapy candidates in a multi-arm Phase 1 clinical trial, we plan to test our series 200 TCR-Ts in combination with other TCRs in the ImmunoBank in patients who are positive for the respective targets of these therapies.

We will also explore three-TCR combinations in patients who are positive for the three respective targets.

1 unchanged sentence

A summary of our planned Phase 1 clinical strategy is shown below.

TSC-200 Series Phase 1 Clinical Strategy

TSC-200 Series Dose Escalation Scheme Provides Rapid Path to Testing and Expanding Multiplexed TCR-T in Phase 1

Anticipated timeline

As we advance our solid tumor program, we anticipate presenting pre-clinical data at a major scientific meeting in the first half of 2022;

filing INDs for two solid tumor TCR-T therapy candidates in the second half of 2022 with additional IND filings in 2023;

and presenting initial clinical data on our multi-arm Phase 1 clinical trial in 2023.

As we advance our solid tumor program, we anticipate submitting IND filings for additional TCRs throughout 2023.

We expect to report initial safety data for the most advanced TCRs in this series by year end 2023, with multiplex therapy data anticipated in 2024.

As we continue to discover and validate TCR/target pairs, we aim to continue to file additional INDs and introduce those solid tumor TCR-T therapy candidates into this multi-arm basket-style Phase 1 clinical trial.

We believe this trial will serve as the first step towards our long-term goal of building and expanding ImmunoBank to provide customized multiplexed TCR-T therapy for virtually any patient with a solid tumor malignancy.

We believe this trial will serve as the first step towards our long-term goal of building and expanding the ImmunoBank to provide customized multiplexed TCR-T therapy for virtually any patient with a solid tumor malignancy.

ImmunoBank –

8 unchanged sentences

TCRs that recognize tumor-specific antigens on cancer cells without recognizing problematic off-targets.

As we advance our ImmunoBank of TCRs through clinical development, we intend to continue to build our own manufacturing platform, while simultaneously investigating novel T cell engineering platforms once they have established safety and efficacy.

As we advance the ImmunoBank of TCRs through clinical development, we intend to continue to build our own manufacturing platform, while simultaneously investigating novel T cell engineering platforms once they have established safety and efficacy.

Ultimately, we aspire to build the largest collection of validated TCR “content”

5 unchanged sentences

We intend to build additional corporate value by opportunistically pursuing collaborations with strategic partners for applications of our platform technologies outside our core focus.

As a proof-of-concept for TargetScan’s applicability and antigen discovery capabilities in infectious disease, we applied our technology to identify the antigens most frequently recognized by the T cells of patients who had recovered from COVID-19.

We screened the entire genome of SARS-CoV-2, the virus that causes COVID-19, as well as the genomes of SARS-CoV and the four seasonal coronaviruses that cause the common cold.

We found that the antigens recognized by CD8+ T cells were largely derived from segments of the virus that are not part of the spike protein, which is the current target of COVID-19 vaccines.

Additionally, patient T cells were generally not found to be cross-reactive with seasonal coronaviruses, suggesting that prior coronavirus exposure is unlikely to confer immunity to COVID-19.

We published the details of these studies in the journal Immunity in 2020.

T Cell Targets in SARS-CoV-2 Are Primarily Located

In Proteins Other Than the Spike Protein

We have partnered with QIAGEN Sciences, LLC to develop a highly specific diagnostic test to determine prior exposure to the virus based upon the presence of anti-viral T cells.

We believe that our findings can also be used to develop next-generation vaccines for COVID-19 that confer durable immune protection from SARS-CoV-2 infection and potentially provide protection against future variants.

Most current vaccine efforts elicit a response to the SARS-CoV-2 spike protein.

While these first-generation vaccines are able to elicit neutralizing antibodies and provide effective protection against infection, it is not clear how durable these responses will be given that antibody levels have been shown to rapidly decline after a few months and numerous coronavirus variants have now been discovered with mutations in the spike protein.

Notably, none of the mutations observed in these variants occurs in the 29 T cell targets that we identified, suggesting that vaccines delivering these target antigens may be less susceptible to vaccine-resistant strains emerging in the future.

We have partnered with Akagera Medicines to develop an mRNA lipid nanoparticle (LNP) vaccine candidate which includes not only the spike protein that elicits neutralizing antibodies but also all the non-spike T cell epitopes we discovered which would elicit a protective T cell response.

The LNP vaccine candidate utilizes Akagera’s novel LNP technology which is designed to better target lymph nodes thereby reducing the risk of local toxicity such as injection site swelling, reduce the vaccine dose by up to 10-fold and have improved stability requiring a -20 °

C cold chain rather than the more onerous -80 °

C cold chain that existing mRNA LNP vaccines require.

Preclinical testing of this vaccine candidate has demonstrated efficient eliciting of a broad T cell response mimicking the T cell responses observed in convalescent COVID-19 patients.

Other Diseases

8 unchanged sentences

(Novartis) (such agreement, the Novartis Agreement).

Pursuant to the Novartis Agreement, we have received an aggregate of $20.0 million of cash representing the upfront payment and have receivables for reimbursement of expenditures under the arrangement of $0.9 million as of December 31, 2021.

Pursuant to the Novartis Agreement, we have received an aggregate of $20.0 million of cash representing the upfront payment and research funding totalling $10 million.

We granted Novartis and its affiliates options to obtain exclusive, royalty-bearing, sublicensable, transferable, worldwide licenses to certain target antigens identified in performance of the Novartis Agreement and corresponding T cell receptors for such target antigens to make, have made, import, use, sell or offer for sale, including to develop, manufacture, commercialize, register, hold or keep, have used, export, transport, distribute, promote, market or have sold or otherwise dispose of such target antigens and corresponding T cell receptors.

1 unchanged sentence

In addition, we granted Novartis and its affiliates an option to obtain a non-exclusive, royalty-bearing, sublicensable, transferable, worldwide license under our intellectual property corresponding to products associated with such Optioned Program and improvements to our platform created in performance of activities under the Novartis Agreement, in each case, solely as necessary to exploit products associated with such Optioned Program.

The ownership of inventions (and resulting patent rights) created in performance of the collaboration will be determined by inventorship (i.e., inventions invented solely by us in performance of the collaboration and inventions invented solely by Novartis in performance of the collaboration will be owned by Novartis and inventions invented jointly by us and Novartis in performance of the collaboration will be jointly owned).

collaboration will be jointly owned).

We retain our rights to (i) our intellectual property, (ii) programs that are not selected by Novartis and (iii) our platform improvements, which will not be considered collaboration technology.

15 unchanged sentences

provided, however, that Novartis will be required to fulfill any payment obligations that accrued prior to termination.

For a period of up to 180 days after the end of the collaboration period (which collaboration period will end no later than March 2023), we agree to notify Novartis if we intend to seek a third party partner to exclusively license or similarly grant rights to patents or know-how developed by us under the collaboration to allow for the development or commercialization of products directed to any programs that Novartis has not exercised an option to prior to the expiration of such option (a ROFN Notice).

For a period of up to 180 days after the end of the collaboration period (which collaboration period is anticipated to end in March 2023), we agree to notify Novartis if we intend to seek a third party partner to exclusively license or similarly grant rights to patents or know-how developed by us under the collaboration to allow for the development or commercialization of products directed to any programs that Novartis has not exercised an option to prior to the expiration of such option (a ROFN Notice).

Upon receiving such notice, Novartis will have 90 days to provide us with a term sheet to exclusively license such collaboration technology to develop or commercialize products directed to such previously declined program, which will trigger Novartis’s right of first negotiation.

If Novartis delivers such term sheet, then Novartis will have 270 days following the ROFN Notice to negotiate a license for such collaboration technology.

The Novartis Agreement will remain in effect until (i) all options expire unexercised or (ii) if any options are exercise, on a product-by-product and country-by-country basis for each Optioned Program, upon the expiration of the Royalty Term for all products

associated with such Optioned Program in such country.

Either party may terminate the Novartis Agreement upon an uncured material breach of the agreement or insolvency of the other party.

3 unchanged sentences

Exclusive Patent License Agreement with BWH

On December 5, 2018, we entered into an Exclusive Patent License Agreement with The Brigham and Women’s Hospital, Inc.

(“BWH”), as amended on July 26, 2019 and further amended and restated on April 20, 2021 (collectively, the “BWH Agreement”), pursuant to which we obtained an exclusive, sublicensable, worldwide license to practice under certain of BWH’s patent rights for identifying T Cell epitopes, which are relevant to our TargetScan technology for identifying potential therapeutic products.

The original 2018 BWH Agreement granted us the right to practice BWH’s patent rights in a certain field of use (“MHC Class I License Field”).

On December 5, 2018, we entered into an Exclusive Patent License Agreement with The Brigham and Women’s Hospital, Inc., or BWH, as amended on July 26, 2019 and further amended and restated on April 20, 2021, or, collectively, the BWH Agreement, pursuant to which we obtained an exclusive, sublicensable, worldwide license to practice under certain of BWH’s patent rights for identifying T Cell epitopes, which are relevant to our TargetScan technology for identifying potential therapeutic products.

The original 2018 BWH Agreement granted us the right to practice BWH’s patent rights in a certain field of use, MHC Class I License Field.

In connection with the amended and restatement of the BWH Agreement in 2021, we expanded the field of use in which we are authorized to practice BWH’s patent rights to include MHC Class II uses and applications in exchange for certain additional payments to BWH.

1 unchanged sentence

Upon execution of the amendment of the BWH Agreement dated April 20, 2021, we paid an additional one-time fee of $466,500.

We are required to pay BWH up to an aggregate of $12.72 million upon the achievement of certain clinical, regulatory and sales milestones for therapeutic products and processes.

We are required to pay BWH up to an aggregate of $12.72 million upon the achievement of certain clinical, regulatory and sales

milestones for therapeutic products and processes.

We are obligated to pay a low double-digit percentage of all non-royalty income we receive under sublicenses of BWH’s patent rights.

We are also obligated to pay a low single-digit percentage of all non-royalty income we receive under agreements with third parties (“Collaborators”) where we practice under BWH’s patent rights in connection with the research or development one or more therapeutic products or processes with or for such third party (“Collaboration Agreements”).

We are also obligated to pay a low single-digit percentage of all non-royalty income we receive under agreements with third parties, or Collaborators, where we practice under BWH’s patent rights in connection with the research or development one or more therapeutic products or processes with or for such third party, or Collaboration Agreements.

We are also obligated to pay tiered royalties in the high single-digit percentage range on annual net sales of products and processes that practice the licensed patent rights and in the low single-digit percentage range on annual net sales of therapeutic and diagnostic products and processes directed to an epitope identified through practicing the licensed patent rights (other than those sold by Collaborators), with the royalty percentage for such products and processes decreasing to lower than one-percent royalties if directed to epitopes identified through practicing the licensed patent rights after December 31, 2019.

15 unchanged sentences

or (5) if we or any of our affiliates challenge the validity, enforceability or scope of any of the patent rights licensed to us under the BWH Agreement.

Option and Exclusive License Agreement with Qiagen

On November 5, 2020, we entered into an Option and Exclusive License Agreement with QIAGEN Sciences, LLC (Qiagen) (such agreement, the Qiagen Agreement).

Pursuant to the Qiagen Agreement, Qiagen paid us a one-time non-refundable, non-creditable $150,000 option fee (Option Fee) in exchange for an option to obtain an exclusive, royalty-bearing, sublicensable, worldwide license under our rights to patents and patent applications related to certain SARS- CoV-2 peptides to use, make and otherwise commercialize products containing such SARS-CoV-2 peptides (the Option).

Qiagen exercised the Option on April 14, 2021 and paid us an additional $150,000 option exercise fee.

Qiagen may freely sublicense its rights through multiple tiers so long as it binds each sublicensee to terms

consistent with the Qiagen Agreement and remains responsible for any breaches of such terms by its sublicensees.

We expressly reserved the right to conduct research or develop or commercialize products for or related to the treatment of SARS-CoV-2.

In addition, Qiagen is required to pay us a one-time, non-refundable, non-creditable $300,000 milestone payment upon launch of the first in vitro diagnostic product containing the licensed peptides.

Qiagen is also required to pay us, on a product-by-product and country-by-country basis, royalties in the low-single-digit to mid-single-digit percentage on Qiagen’s and its affiliates’

net sales of products containing the licensed peptides, subject to certain customary reductions, for as long as such products are covered by a valid claim of the patents licensed by us to Qiagen under the Qiagen Agreement.

We are solely responsible for managing patent maintenance, prosecution and enforcement during the term of both the Option Exercise Period (defined below) and term of the Qiagen Agreement.

The Qiagen Agreement will expire upon the later to occur of (i) expiration of the last to expire valid claim of patents we license to Qiagen under the Qiagen Agreement or (ii) 15 years from the effective date of the Qiagen Agreement.

Should any patents issue from any non-provisional patent applications claiming priority to any of the licensed U.S.

provisional patent applications, the current expected expiration date for the last-to-expire licensed patent right is June 17, 2041 (absent any adjustments or extensions of term).

Qiagen may terminate the Qiagen Agreement for any reason upon 60 days’

prior written notice to us;

provided, however, that Qiagen will be required to fulfill any payment obligations that accrued prior to termination.

Non-Exclusive License Agreement with Provincial Health Services Authority

On October 15, 2020, we entered into a Non-Exclusive License Agreement with the Provincial Health Services Authority of British Columbia (PHSA) (such agreement, the PHSA Agreement).

On October 15, 2020, we entered into a Non-Exclusive License Agreement with the Provincial Health Services Authority of British Columbia, or PHSA, and such agreement, the PHSA Agreement.

Pursuant to the PHSA Agreement, we obtained a non-exclusive, perpetual, non-transferable, sublicensable, worldwide license to practice certain of PHSA’s patent rights for identifying T Cell epitopes, which epitopes are relevant to our platform for identifying potential TCR-T therapies.

28 unchanged sentences

Aldevron has a license from Nature Technology to manufacture research-grade and GMP-grade transposon and transposase.

The initial batch of research-grade and GMP-grade transposon and transposase which we intend to use in connection with our near-term pre-clinical studies and clinical trials will be manufactured by Aldevron pursuant to a non-exclusive, fee-for-service supply arrangement pursuant to which we may purchase materials from time-to-time, subject to normal market pricing.

We are developing our manufacturing process using industry standard instrumentation to enable direct transfer of methods from process development to manufacturing.

14 unchanged sentences

We expect to compete with a number of other T cell therapy companies, including those with target discovery platforms, such as Adaptive Therapeutics, Inc., Immatics N.V., Enara Bio Ltd., Repertoire Immune Medicines, Inc., and 3T Biosciences Inc.

In addition, we may face competition from other TCR companies such as Adaptimmune Therapeutics, Plc., Medigene AG, GlaxoSmithKline Pharmaceuticals Ltd, T-Knife GmbH, and Alaunos Therapeutics, Inc.

In addition, we may face competition from other TCR companies such as Adaptimmune Therapeutics, Plc., Medigene AG, Affini-T Therapeutics, Inc., T-Knife GmbH, and Alaunos Therapeutics, Inc.

We may also face competition from companies focused on CAR-T, TIL, gammadelta T cell, and other T cell therapies, such as Kite Pharma, Inc., a subsidiary of Gilead, Inc.

(including Yescarta, which is approved for the treatment for large B-cell lymphoma or follicular lymphoma, two types of non-Hodgkin lymphoma), Juno Therapeutics, Inc., a subsidiary of Bristol-Myers Squibb, Inc., Iovance Biotherapeutics, Inc., Instil Bio, Inc., Achilles Therapeutics plc, Sana Biotechnology, Inc., 2seventy Bio, Inc., Atara Biotherapeutics, Inc., Lyell Immunopharma, Inc., Allogene Therapeutics, Inc., PACT Pharma, Inc., Gadeta B.V., and Adicet Bio, Inc.

(including Yescarta, which is approved for the treatment for large B cell lymphoma or follicular lymphoma, two types of non-Hodgkin lymphoma), Juno Therapeutics, Inc., a subsidiary of Bristol-Myers Squibb, Inc., Iovance Biotherapeutics, Inc., Instil Bio, Inc., Achilles Therapeutics plc, Sana Biotechnology, Inc., 2seventy Bio, Inc., Atara Biotherapeutics, Inc., Lyell Immunopharma, Inc., Allogene Therapeutics, Inc., Gadeta B.V., and Adicet Bio, Inc.

There are also companies utilizing other cell-based approaches that may be competitive to our product candidates.

1 unchanged sentence

are developing therapies that target and/or engineer natural killer, or NK, cells.

In addition, for our lead liquid tumor programs, TSC-100

and TSC-101, we may face competition from HighPass Bio, Inc.

NexImmune, Inc., VOR Biopharma, Inc., and Marker Therapeutics, Inc., who are also developing cell therapies in the post-HCT setting.

In addition, for our lead programs, TSC-100 and TSC-101, we may face competition from BlueSphere Bio, NexImmune, Inc., VOR Biopharma, Inc., and Marker Therapeutics, Inc., who are also developing cell therapies in the post-HCT setting.

The named companies are not fully inclusive of all possible competitive threats.

Immunocore’s KIMMTRAK is the first TCR-based therapeutic to receive FDA approval, potentially establishing a regulatory pathway, pricing benchmark, and commercial uptake pattern for TCR-based therapeutics.

However, KIMMTRAK is a bispecific antibody indicated for use in a rare patient population with unresectable or metastatic uveal melanoma, which is not directly competitive to TScan.

However, KIMMTRAK is a bispecific antibody indicated for use in a rare patient population with unresectable or metastatic uveal melanoma, which is not directly competitive to TScan and may have different market access and commercial uptake dynamics.

Immunocore’s other programs using TCR-mimic bispecifics in other indications such as cutaneous melanoma may be a more direct competitor to TScan’s products.

17 unchanged sentences

If this were to occur, it could harm our reputation and adversely affect our business, competitive position, financial condition or results of operations.

As of the date hereof, our patent portfolio consisted of a patent family exclusively licensed from BWH, including a pending U.S.

As of the date hereof, our patent portfolio includes a patent family exclusively licensed from BWH, including a pending U.S.

non-provisional patent application and multiple pending foreign non-provisional patent applications, relating to methods and compositions for identifying target antigens specific to T cells.

In addition, we have filed multiple patent families including multiple pending U.S.

In addition, we have filed applications in multiple patent families including multiple pending U.S.

provisional patent applications and more than ten pending international and foreign patent applications.

The claims of these patent applications are directed toward various aspects of our therapy candidates and research programs, including compositions of matter directed to SARS-CoV-2 immunodominant antigens, anti-SARS-CoV-2 TCRs, anti-SARS-CoV-2 vaccines, anti-HA-1 TCRs (including the TSC-100 TCR-T therapy candidate), anti-HA-2 TCRs (including the TSC-101 TCR-T therapy candidate), TCRs targeting the antigen of TSC-200, anti-HPV TCRs (including the TSC-200 TCR-T therapy candidate), and TCRs targeting the antigen of TSC-204 (including the TSC-204 TCR-T therapy candidate), as well as a phospholipid scrambling reporter-based T cell antigen screening platform and certain screening methods thereof.

The claims of these patent applications are directed toward various aspects of our therapy candidates and research programs, including compositions

of matter directed to SARS-CoV-2 immunodominant antigens, anti-SARS-CoV-2 TCRs, anti-SARS-CoV-2 vaccines, anti-HA-1 TCRs (including the TSC-100 TCR-T therapy candidate), anti-HA-2 TCRs (including the TSC-101 TCR-T therapy candidate), anti-HPV TCRs (including the TSC-200 TCR-T therapy candidate), anti-PRAME TCRs (including the TSC-203 TCR-T therapy candidate), and anti-MAGE-A1 TCRs (including the TSC-204 TCR-T therapy candidate), as well as platform technologies including a phospholipid scrambling reporter-based T cell antigen screening platform and certain screening methods thereof, and a TCR multiplexing platform and certain therapeutic methods thereof.

These patent applications, if issued, are expected to expire on various dates from 2038 through 2043, in each case without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid.

Liquid Tumor Program Product Patent Families

We have filed multiple pending patent applications covering our liquid tumor programs including claims to the composition-of-matter of TSC-100, TSC-101, as well as other anti-HA-1 and anti-HA-2 TCRs and related T cell therapies.

The pending patent

applications will begin to enter the PCT international phase by April 2022.

The pending international Patent Cooperation Treaty (PCT), Argentine, and Taiwanese patent applications claim the benefit of priority from earlier-filed U.S.

Hematologic Malignancies Program Product Patent Families

We have filed multiple pending patent applications covering aspects of our hematologic malignancies programs including claims to the composition-of-matter of TSC-100, TSC-101, and other anti-HA-1 and anti-HA-2 TCRs and related T cell therapies.

The pending international Patent Cooperation Treaty (PCT) application will begin to enter the national and regional phases by May 2023.

The pending international Patent Cooperation Treaty (PCT), Australian, Argentine, and Taiwanese patent applications claim the benefit of priority from earlier-filed U.S.

priority provisional patent applications filed in 2020 and 2021.

We expect any patents within this family, if issued, to expire the earliest in 2041 (without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid).

We expect the issued Australian patent and any additional patents within this family, if issued, to expire no earlier than 2041 (without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid).

Solid Tumor Program Product Patent Families

We have filed multiple pending U.S.

provisional patent applications covering our solid tumor programs including claims to the composition-of-matter of anti-HPV, anti-MAGE-A1 TCRs and related T-cell therapies.

The pending patent applications will begin to enter the PCT international phase by April 2022.

We expect any patents within this family, if issued, to expire the earliest in 2042 (without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid).

provisional and PCT international patent applications covering aspects of our solid tumor programs including claims to the composition-of-matter of anti-HPV, anti-PRAME, anti-MAGE-A1 TCRs, and related T cell therapies.

The pending patent applications will begin to enter the national and regional phases by October 2023.

We expect any patents within this family, if issued, to expire no earlier than 2042 (without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid).

Infectious Disease Product Patent Families

We have filed multiple pending patent applications covering our infectious disease programs including claims to the composition-of-matter of SARS-CoV-2 immunodominant antigens, anti-SARS-CoV-2 TCRs, and composition-of-matter of certain SARS-CoV-2 vaccines.

These pending international PCT, Argentine, Bangladeshi, Democratic Republic of the Congo, Pakistani, and Taiwanese patent applications claim the benefit of priority from earlier-filed U.S.

We have filed multiple pending patent applications covering aspects of our infectious disease programs including claims to the composition-of-matter of SARS-CoV-2 immunodominant antigens, anti-SARS-CoV-2 TCRs, and the composition-of-matter of certain SARS-CoV-2 vaccines.

These pending international PCT, U.S., Australian, Canadian, European, Argentine, Bangladeshi, Democratic Republic of the Congo, Pakistani, and Taiwanese patent applications claim the benefit of priority from earlier-filed U.S.

priority provisional patent applications filed in 2020.

Certain of these pending patent applications are jointly owned by us and AHS Hospital Corporation (“AHS”).

AHS has exclusively licensed their interest to us in such patent applications.

We expect the issued Australian patent, the Democratic Republic of the Congo patent, and any additional patents within this family, if issued, to expire no earlier than 2041 (without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid).

Certain of these pending patent applications are jointly owned by us and AHS Hospital Corporation, or AHS.

AHS has exclusively licensed their interest in such patent applications to us.

Platform Technology

We own a pending PCT patent application with claims that cover reporter-based T cell antigen screening platform.

We expect any claims within this family, if issued, to expire the earliest in 2041 (without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid).

Our pending patent applications may not result in issued patents and we can give no assurance that any patents that might issue in the future will protect our future products or provide us with any competitive advantage.

We own a pending PCT patent application with claims that cover aspects of our reporter-based T cell antigen screening platform.

We expect any claims within this family, if issued, to expire no earlier than 2041 (without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid).

We also own a family of pending provisional patent applications with claims that cover multiplexed TCR compositions and certain therapeutic methods thereof.

We expect any claims within this family, if issued, to expire no earlier than 2043 (without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid).

Our pending patent applications may not result in issued patents and we can give no assurance that any patents that might issue in the future will protect our products or provide us with any competitive advantage.

Moreover, U.S.

2 unchanged sentences

provisional patent applications, if we do not timely file any non-provisional patent applications, we may lose our priority date with respect to our provisional patent applications and any patent protection on the inventions disclosed in our provisional patent applications.

While we intend to timely file non-provisional patent applications relating to our provisional patent applications, we cannot predict whether any such patent applications will result in the issuance of patents that provide us with any competitive advantage.

While we generally intend to timely file non-provisional patent applications relating to our provisional patent applications, we cannot predict whether any such patent applications will result in the issuance of patents that provide us with any competitive advantage.

For more information regarding the risks related to our intellectual property, please see “Risk Factors—Risks Related to Our Intellectual Property”.

We rely on certain technology and intellectual property rights that we in-license from third parties.

Third-Party Intellectual Property Rights

For certain aspects of our business, we rely on certain technology and intellectual property rights that we in-license from third parties.

We have an exclusive patent license from The Brigham and Women’s Hospital, Inc.

(BWH) to a patent family directed to a granzyme B (GzB)-based antigen screening technology platform, as well as compositions-of-matter and certain screening methods thereof (consisting of one pending U.S.

(BWH) to a patent family directed to aspects of a granzyme B (GzB)-based antigen screening technology platform, as well as compositions-of-matter and certain screening methods thereof (consisting of one pending U.S.

patent application and six foreign patent applications pending in Australia, Canada, China, Europe, Hong Kong, and Japan).

Any patents issuing from the U.S.

and foreign patent applications are expected to expire in 2038 (without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid).

and foreign patent applications are expected to expire no earlier than 2038 (without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid).

We also have a non-exclusive, perpetual, non-transferable patent license from the Provincial Health Services Authority of British Columbia (PHSA) to a patent family directed to granzyme-based antigen screening methods consisting of an issued U.S.

patent that is expected to expire August 4, 2035, a pending U.S.

patent that is expected to expire on August 4, 2035 (assuming that appropriate maintenance and governmental fees are paid), a pending U.S.

patent application, and issued Canadian patent that is expected to expire March 25, 2035 (assuming that appropriate maintenance and governmental fees are paid).

We do not have any additional material licenses to any technology or intellectual property rights.

As of the date hereof, we own or have rights to two pending U.S.

trademark applications, 14 foreign trademark registrations, and three pending foreign trademark applications.

As of the date hereof, we own or have rights to U.S.

and foreign trademark registrations and applications that cover certain aspects of our business.

Government Regulation

FDA Regulation and Marketing Approval

In the U.S., the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (“FDCA”), and biologics under the Public Health Service Act, the regulations promulgated under both laws and other federal, state, and local statutes and regulations.

In the U.S., the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act, or FDCA, and biologics under the Public Health Service Act, the regulations promulgated under both laws and other federal, state, and local statutes and regulations.

Failure to comply with the applicable U.S.

4 unchanged sentences

The FDA and comparable regulatory agencies in state and local jurisdictions and in foreign countries impose substantial requirements upon the clinical development, approval, manufacture, distribution and marketing of pharmaceutical products.

These agencies and other federal, state and local entities regulate R&D activities and the testing, manufacture, quality control, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, post-approval monitoring, advertising, promotion, sampling and import and export of our products.

These agencies and other federal, state and local entities regulate research and development activities and the testing, manufacture, quality control, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, post-approval monitoring, advertising, promotion, sampling and import and export of our products.

Rocket’s drugs must be approved by the FDA as biologics through the BLA approval process applicable to gene therapy product candidates, before they may be legally marketed in the U.S.

Within the FDA, the FDA’s Center for Biologics Evaluation and Research (“CBER”) regulates gene therapy products and has published guidance documents with respect to the development these types of products.

Within the FDA, the FDA’s Center for Biologics Evaluation and Research, or CBER, regulates gene therapy products and has published guidance documents with respect to the development these types of products.

The FDA also has published guidance documents related to, among other things, gene therapy products in general, their preclinical assessment, observing subjects involved in gene therapy studies for delayed adverse events, potency testing, and chemistry, manufacturing and control information in gene therapy INDs.

The process required by the FDA before a biologic may be marketed in the United States generally involves the following:

completion of non-clinical laboratory tests, animal studies and formulation studies conducted according to Good Laboratory Practice (“GLP”), or other applicable regulations;

completion of non-clinical laboratory tests, animal studies and formulation studies conducted according to Good Laboratory Practice, or GLP, or other applicable regulations;

submission of an IND, which allows clinical trials to begin unless FDA objects within 30 days;

performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the proposed drug or biologic for its intended use or uses conducted in accordance with FDA regulations and Good Clinical Practices (“GCP”), which are international ethical and scientific quality standards meant to ensure that the rights, safety and well-being of trial participants are protected, and that the integrity of the data is maintained;

performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the proposed drug or biologic for its intended use or uses conducted in accordance with FDA regulations and Good Clinical Practices, or GCP, which are international ethical and scientific quality standards meant to ensure that the rights, safety and well-being of trial participants are protected, and that the integrity of the data is maintained;

preparation and submission to the FDA of a BLA;

1 unchanged sentence

review of the product by an FDA advisory committee, where appropriate or if applicable;

satisfactory completion of pre-approval inspection of manufacturing facilities and clinical trial sites at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practice (“cGMP”) requirements, and if applicable, the FDA’s current Good Tissue Practice (“cGTP”) requirements, and of selected clinical trial sites to assess compliance with GCP requirements;

satisfactory completion of pre-approval inspection of manufacturing facilities and clinical trial sites at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practice, or cGMP, requirements, and if applicable, the FDA’s current Good Tissue Practice, or cGTP, requirements, and of selected clinical trial sites to assess compliance with GCP requirements;

FDA approval of a BLA which must occur before a biologic can be marketed or sold.

3 unchanged sentences

The results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical studies, among other things, are submitted to the FDA as part of an IND.

Companies usually must complete some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity and must also develop additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the drug in commercial quantities in accordance with (“cGMP”) requirements.

The manufacturing process must be capable of consistently producing quality batches of the drug candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality, and purity of the final drug product.

Additionally, appropriate packaging must be

selected and tested, and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

IND and Clinical Trials

6 unchanged sentences

Accordingly, submission of an IND may or may not result in the FDA allowing clinical trials to commence or continue.

In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules are subject to oversight of institutional biosafety committees(“IBC’s”), as set forth in the National Institutes for Health(“NIH”), Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines.

In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules are subject to oversight of institutional biosafety committees, or IBC’s, as set forth in the National Institutes for Health, or NIH, Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines.

Under the NIH Guidelines, recombinant and synthetic nucleic acids are defined as:

9 unchanged sentences

A separate submission to the existing IND must be made for each successive clinical trial to be conducted during product development.

Further, an independent Institutional Review Board (“IRB”) for each site at which the clinical trial will be conducted must review and approve the clinical trial before it commences at that site.

Further, an independent Institutional Review Board, or IRB, for each site at which the clinical trial will be conducted must review and approve the clinical trial before it commences at that site.

Informed written consent must also be obtained from each trial subject.

10 unchanged sentences

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.

Phase 1, Phase 2 and Phase 3 clinical trials may not be

completed successfully within any specified period, or at all.

Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all.

Government regulation may delay or prevent marketing of product candidates or new drugs for a considerable period of time and impose costly procedures upon our activities.

18 unchanged sentences

The resubmitted application also is subject to review before the FDA accepts it for filing.

The FDA has 60 days from its receipt of a BLA to conduct an initial review to determine whether the application will be accepted for filing based on the agency’s threshold determination that the application is sufficiently complete to permit substantive review.

sufficiently complete to permit substantive review.

The FDA reviews a BLA to determine, among other things, whether the proposed product is safe and potent, or effective, for its intended use, and has an acceptable purity profile, and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, safety, strength, quality, potency and purity.

11 unchanged sentences

For a gene therapy product, the FDA also will not approve the product if the manufacturer is not in compliance with the cGTPs.

human cells or tissue intended for implantation, transplant, infusion, or transfer into a human recipient.

These are FDA regulations that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissues, and cellular and tissue-based products, or HCT/Ps, which are human cells or tissue intended for implantation, transplant, infusion, or transfer into a human recipient.

The primary intent of the +cGTP requirements is to ensure that cell and tissue-based products are manufactured in a manner designed to prevent the introduction, transmission and spread of communicable disease.

9 unchanged sentences

See “Post-Marketing Requirements”

The FDA also has authority to require a Risk Evaluation and Mitigation Strategy (“REMS”), from manufacturers to ensure that the benefits of a drug outweigh its risks.

The FDA also has authority to require a Risk Evaluation and Mitigation Strategy, or REMS, from manufacturers to ensure that the benefits of a drug outweigh its risks.

A sponsor may also voluntarily propose a REMS as part of the BLA submission.

1 unchanged sentence

Based on statutory standards, elements of a REMS may include “Dear Doctor letters,”

a medication guide, more elaborate targeted educational programs, and in some cases distribution and use restrictions, referred to as elements to assure safe use (“ETASU”).

a medication guide, more elaborate targeted educational programs, and in some cases distribution and use restrictions, referred to as elements to assure safe use, or ETASU.

ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring and the use of patient registries.

4 unchanged sentences

Even if a product candidate receives regulatory approval, the approval may be limited to specific disease states, patient populations and dosages, or might contain significant limitations on use in the form of warnings, precautions or contraindications, or in the form of onerous risk management plans, restrictions on distribution or use, or post-marketing trial requirements.

Further, even after regulatory approval is obtained, later discovery of previously unknown problems with a product may result in restrictions on the product, including safety labeling or imposition of a REMS, the requirement to conduct post-market studies or clinical trials or even complete withdrawal of the product from the market.

Further, even after regulatory

approval is obtained, later discovery of previously unknown problems with a product may result in restrictions on the product, including safety labeling or imposition of a REMS, the requirement to conduct post-market studies or clinical trials or even complete withdrawal of the product from the market.

Delay in obtaining, or failure to obtain, regulatory approval for our products, or obtaining approval but for significantly limited use, would harm our business.

8 unchanged sentences

Market Exclusivity

The Affordable Care Act, or ACA, signed into law on March 23, 2010, includes a subtitle called the Biologics Price Competition and Innovation Act of 2009, or the BPCIA, which created an abbreviated approval pathway for biological products shown to be similar to, or interchangeable with, an FDA-approved reference biological product.

The Patient Protection and Affordable Care Act, as amended by the Health Care Education and Reconciliation Act, or, collectively, the ACA, signed into law on March 23, 2010, includes a subtitle called the Biologics Price Competition and Innovation Act of 2009, or the BPCIA, which created an abbreviated approval pathway for biological products shown to be similar to, or interchangeable with, an FDA-approved reference biological product.

Bio similarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical trial or trials.

Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously

administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

However, complexities associated with the larger, and often more complex, structure of biological products, as well as the process by which such products are manufactured, pose significant hurdles to implementation that are still being worked out by the FDA.

14 unchanged sentences

If a product with orphan status receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, meaning that FDA may not approve any other applications to market the same drug or biologic product for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity or if the party holding the exclusivity fails to assure the availability of sufficient quantities of the drug to meet the needs of patients with the disease or condition for which the drug was designated.

Competitors, however, may receive approval of different products for the same indication than that for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity.

Competitors, however, may receive approval of different products for the same indication than that for which the orphan product has exclusivity or obtain approval for the same product

but for a different indication for which the orphan product has exclusivity.

Orphan medicinal product status in the EU has similar, but not identical, benefits.

5 unchanged sentences

defined to mean a serious or life-threatening disease in which the serious of life-threatening manifestations primarily affect individuals aged from birth to 18 years and the disease affects fewer than 200,000 individuals in the United States or affects more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making in the United States a drug or biological product for such disease or condition will be received from sales in the United States of such drug or biological product.

The sponsor of a product candidate for a rare pediatric disease may be eligible for a voucher that can be used to obtain a priority review for a subsequent human drug or biological product application after the date of approval of the rare pediatric disease drug or biological product, referred to as a priority review voucher (“PRV”).

A sponsor may request rare pediatric disease designation from the FDA prior to the submission of its BLA.

5 unchanged sentences

FDA is authorized to expedite the review of BLAs in several ways.

Under the Fast Track program, the sponsor of a biologic product candidate may request FDA to designate the product for a specific indication as a Fast Track product concurrent with or after

the filing of the IND.

Under the Fast Track program, the sponsor of a biologic product candidate may request FDA to designate the product for a specific indication as a Fast Track product concurrent with or after the filing of the IND.

Biologic products are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to address unmet medical needs for the condition.

1 unchanged sentence

In addition to other benefits, such as the ability to have greater interactions with FDA, FDA may initiate review of sections of a Fast-Track BLA before the application is complete, a process known as rolling review.

Any product submitted to FDA for marketing, including under a Fast Track program, may be eligible for other types of FDA programs intended to expedite development and review, such as regenerative medicine advanced therapy (“RMAT”) designation, priority review and accelerated approval.

Any product submitted to FDA for marketing, including under a Fast Track program, may be eligible for other types of FDA programs intended to expedite development and review, such as regenerative medicine advanced therapy, or RMAT, designation, priority review and accelerated approval.

To qualify for RMAT designation, the product candidate must be a regenerative medicine therapy, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of Title 21, Code of Federal Regulations;

9 unchanged sentences

FDA aims to complete its review of priority review applications within six months as opposed to 10 months for standard review.

Additionally, a biologic product may be eligible for accelerated approval if it is designed to treat a serious or life-threatening disease or condition and demonstrates an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity and prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, FDA may require that a sponsor of a drug or biologic product candidate receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

In addition, FDA currently requires, unless otherwise informed by the agency, pre-approval of promotional materials intended for dissemination or publication within 120 days of marketing approval .

account the severity, rarity and prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, FDA may require that a sponsor of a drug or biologic product candidate receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials and, under the Food and Drug Omnibus Reform Act of 2022, or FDORA, the FDA is now permitted to require, as appropriate, that such trials be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval.

Under FDORA, the FDA has increased authority for expedited procedures to withdraw approval of a drug or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product.

In addition, FDA currently requires, unless otherwise informed by the agency, pre-approval of promotional materials intended for dissemination or publication .

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or the time period for FDA review or approval may not be shortened.

Fast Track designation, priority review and accelerated approval do not change the standards for approval but may expedite the development or approval process.

Additionally, under FDORA, a platform technology incorporated within or utilized by a biological product is eligible for designation as a designated platform technology if (1) the platform technology is incorporated in, or utilized by, a biological product approved under a BLA;

(2) preliminary evidence submitted by the sponsor of the licensed biological product, or a sponsor that has been granted a right of reference to data submitted in the application for such biological product, demonstrates that the platform technology has the potential to be incorporated in, or utilized by, more than one biological product without an adverse effect on quality, manufacturing, or safety;

and (3) data or information submitted by the applicable person indicates that incorporation or utilization of the platform technology has a reasonable likelihood to bring significant efficiencies to the biological product development or manufacturing process and to the review process.

A sponsor may request the FDA to designate a platform technology as a designated platform technology concurrently with, or at any time after, submission of an IND application for a biological product that incorporates or utilizes the platform technology that is the subject of the request.

If so designated, the FDA may expedite the development and review of any subsequent original BLA for a biological product that uses or incorporates the platform technology.

Designated platform technology status does not ensure that a biological product will be developed more quickly or receive FDA approval.

In addition, the FDA may revoke a designation if the FDA determines that a designated platform technology no longer meets the criteria for such designation.

Post-Marketing Requirements

9 unchanged sentences

The FDA regulations require that products be manufactured in specific approved facilities and in accordance with cGMP.

cGMP regulations

require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.

3 unchanged sentences

BLA holders using contract manufacturers, laboratories or packagers are responsible for the selection and monitoring of qualified firms, and, in certain circumstances, qualified suppliers to these firms.

These firms and, where applicable, their suppliers are subject to inspections by the FDA at any time, and the discovery of violative conditions, including failure to conform to cGMP, could result in enforcement actions that interrupt the operation of any such product or may result in restrictions on a product, manufacturer, or holder of an approved BLA, including, among other things, recall or withdrawal of the product from the market.

These firms and, where applicable, their suppliers are subject to inspections by the

FDA at any time, and the discovery of violative conditions, including failure to conform to cGMP, could result in enforcement actions that interrupt the operation of any such product or may result in restrictions on a product, manufacturer, or holder of an approved BLA, including, among other things, recall or withdrawal of the product from the market.

In addition, the manufacturer and/or holder of an approved BLA are subject to annual product and establishment fees.

9 unchanged sentences

Therefore, our products, once approved, may not obtain market acceptance unless coverage is provided, and reimbursement is adequate to cover a significant portion of the cost of our products.

Factors payors consider in determining reimbursement are based on whether the product is:

a covered benefit under its health plan;

safe, effective and medically necessary;

appropriate for the specific patient;

cost-effective;

neither experimental nor investigational.

In the U.S., no uniform policy of coverage and reimbursement for drug or biological products exists.

The process for determining whether a third-party payor will provide coverage for a drug product typically is separate from the process for setting the price of a drug product or for establishing the reimbursement rate that the payor will pay for the drug product once coverage is approved.

10 unchanged sentences

The American Recovery and Reinvestment Act of 2009 provided funding for the federal government to compare the effectiveness of different treatments for the same illness.

The plan for the research was published in 2012 by the Department of Health and Human Services, the Agency for Healthcare Research and Quality and the National Institutes for Health, and periodic reports on the status of

the research and related expenditures will be made to Congress.

The plan for the research was published in 2012 by the Department of Health and Human

Services, the Agency for Healthcare Research and Quality and the National Institutes for Health, and periodic reports on the status of the research and related expenditures will be made to Congress.

Although the results of the comparative effectiveness studies are not intended to mandate coverage policies for public or private payors, it is not clear what effect, if any, the research will have on the sales of our product candidates, if any such product or the condition that it is intended to treat is the subject of a study.

11 unchanged sentences

Department of Health and Human Services (e.g., the Office of Inspector General), the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency, state Attorneys General and other state and local government agencies.

Our current and future business activities, including for example, sales, marketing, and scientific/educational grant programs must comply with healthcare regulatory laws, as applicable, which may include the Federal Anti-Kickback Statute, the Federal False Claims Act, as amended, the privacy and security regulations promulgated under the Health Insurance Portability and Accountability Act (“HIPAA”), as amended, physician payment transparency laws, and similar state laws.

Our current and future business activities, including for example, sales, marketing, and scientific/educational grant programs must comply with healthcare regulatory laws, as applicable, which may include the Federal Anti-Kickback Statute, the Federal False Claims Act, as amended, the privacy and security regulations promulgated under the Health Insurance Portability and Accountability Act, or HIPAA, as amended, physician payment transparency laws, and similar state laws.

Pricing and rebate programs must comply with the Medicaid Drug Rebate Program requirements of the Omnibus Budget Reconciliation Act of 1990, as amended, and the Veterans Health Care Act of 1992, as amended.

10 unchanged sentences

Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of its facts and circumstances.

Additionally, the intent standard under the Federal Anti-Kickback Statute was amended by the Patient Protection and Affordable Care Act, as amended by the Health Care Education and Reconciliation Act (collectively, the “ACA”), to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

Additionally, the intent standard under the Federal Anti-Kickback Statute was amended by the ACA, to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

In addition, the ACA codified case law that a claim including items or services resulting from a violation of the Federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the Federal False Claims Act.

2 unchanged sentences

Some of these state prohibitions apply to the referral of patients for healthcare services reimbursed by any insurer, not just federal healthcare programs such as Medicare and Medicaid.

Due to the breadth of these federal and state anti-kickback laws, and the potential for additional legal or regulatory change in this area, it is possible that our future business activities, including our sales and marketing practices and/or our future relationships with physicians and the medical community might be challenged under anti-kickback laws, which could harm us.

Due to the breadth of these federal and state anti-kickback laws, and the potential for additional legal or regulatory change in

this area, it is possible that our future business activities, including our sales and marketing practices and/or our future relationships with physicians and the medical community might be challenged under anti-kickback laws, which could harm us.

Federal false claims and false statement laws, including the civil False Claims Act, prohibits any person or entity from, among other things, knowingly presenting, or causing to be presented, for payment to federal programs (including Medicare and Medicaid) claims for items or services, including drugs, that are false or fraudulent.

7 unchanged sentences

Additionally, HIPAA created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing, or covering up a material fact or making any materially false, fictitious, or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

There are also an increasing number of state laws that require manufacturers to make reports to states on pricing and marketing information.

1 unchanged sentence

For example, federal government price reporting laws, which require us to calculate and report complex pricing metrics in an accurate and timely manner to government programs.

In addition, as discussed below, a similar federal requirement under the Physician Payments Sunshine Act, requires certain manufacturers to track and report to the federal government certain payments provided to physicians and teaching hospitals made in the previous calendar year, as well as certain ownership and investment interests held by physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors) and their immediate family members.

In addition, as discussed below, a similar federal requirement under the Physician Payments Sunshine Act, requires certain manufacturers to track and report to the federal government certain payments provided to physicians, certain other licensed health care practitioners and teaching hospitals made in the previous calendar year, as well as certain ownership and investment interests held by physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors) and their immediate family members.

These laws may affect our sales, marketing, and other promotional activities by imposing administrative and compliance burdens on us.

In addition, given the lack of clarity with respect to these laws and their implementation, our reporting actions could be subject to the penalty provisions of the pertinent state and federal authorities.

Effective January 1, 2022, these reporting obligations extend to include transfers of value made to certain non-physician providers such as physician assistants and nurse practitioners.

In addition, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and their respective implementing regulations, including the Final Omnibus Rule published on January 25, 2013, imposes specified requirements relating to the privacy, security, and transmission of individually identifiable health information on certain types of individuals and organizations.

In addition, certain state laws govern the privacy and security of health information in certain circumstances, many of which differ from each other and from HIPAA in significant ways and may not have the same effect, thus complicating compliance efforts.

Further, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and their respective implementing regulations, including the Final Omnibus Rule published on January 25, 2013, imposes specified requirements relating to the privacy, security, and transmission of individually identifiable health information on certain types of individuals and organizations.

HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’

fees and costs associated with pursuing federal civil actions.

In addition, there may be other federal, state and non-U.S.

laws which govern the privacy and security of health and other personal information in certain circumstances, many of which differ from each other and from HIPAA in significant ways and may not have the same effect, thus complicating compliance efforts.

The failure to comply with regulatory requirements subjects us to possible legal or regulatory action.

10 unchanged sentences

In particular, in 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the ACA, was enacted, which, among other things, subjected biologic products to potential competition by lower-cost biosimilars;

addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;

increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program;

1 unchanged sentence

subjected manufacturers to new annual fees and taxes for certain branded prescription drugs;

created a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% (increased to 70% pursuant to the Bipartisan Budget Act of 2018, effective as of January 1, 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;

created a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;

and provided incentives to programs that increase the federal government’s comparative effectiveness research.

Since its enactment, there have been judicial, Congressional, and executive challenges to certain aspects of the ACA.

On June 17, 2021, the U.S.

Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Prior to the Supreme Court’s decision, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

It is unclear how other healthcare reform measures of the Biden administration or other efforts, if any, to challenge, repeal or replace the ACA will impact our business.

In addition, other legislative changes have been proposed and adopted since the ACA was enacted.

In August 2011, President Obama signed into law the Budget Control Act of 2011, which, among other things, created the Joint Select Committee on Deficit Reduction to recommend to Congress proposals for deficit reduction of at least $1.2 trillion for the years 2013 through 2021.

The Joint Select Committee on Deficit Reduction did not achieve a targeted deficit reduction, which triggered the legislation’s automatic reduction to several government programs.

This includes aggregate reductions to Medicare payments to providers of, up to 2% per fiscal year, and, due to subsequent legislative amendments, will remain in effect through 2030 unless Congress takes additional action.

These reductions went into effect in April 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2030 unless additional action is taken by Congress.

Pursuant to the Coronavirus Aid, Relief, and Economic Security Act, also known as the CARES Act, as well as subsequent legislation, these reductions have been suspended from May 1, 2020 through March 31, 2022 due to the COVID-19 pandemic.

Then, a 1% payment reduction will occur beginning April 1, 2022 through June 30, 2022, and the 2% payment reduction will resume on July 1, 2022.

In January 2013, the American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers, including hospitals and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Other legislative changes have been proposed and adopted since the ACA was enacted.

The Budget Control Act of 2011, which, among other things, created measures for spending reductions by Congress.

This includes aggregate reductions of Medicare payments to providers of 2% per fiscal year.

Subsequent legislation extended the 2% reduction which remains in effect through 2031.

Due to the Statutory Pay-As-You-Go Act of 2010, estimated budget deficit increases resulting from the American Rescue Plan Act of 2021, and subsequent legislation, Medicare payments to providers will be further reduced starting in 2025 absent further legislation.

The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

On April 13, 2017, CMS published a final rule that gives states greater flexibility in setting benchmarks for insurers in the individual and small group marketplaces, which may have the effect of relaxing the essential health benefits required under the ACA for plans sold through such marketplaces.

4 unchanged sentences

On May 23, 2019, CMS published a final rule to allow Medicare Advantage Plans the option of using step therapy for Part B drugs beginning January 1, 2020.

On December 20, 2019, former President Trump signed into law the Further Consolidated Appropriations Act (H.R.

1865), which repealed the Cadillac tax, the health insurance provider tax, and the medical device excise tax.

It is impossible to determine whether similar taxes could be instated in the future.

There has been increasing legislative and enforcement interest in the United States with respect to specialty drug pricing practices.

Specifically, there have been several recent U.S.

Congressional inquiries and proposed federal and state legislation designed to, among

other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

At a federal level, President Biden signed an Executive Order on July 9, 2021 affirming the administration’s policy to (i) support legislative reforms that would lower the prices of prescription drug and biologics, including by allowing Medicare to negotiate drug prices, by imposing inflation caps, and, by supporting the development and market entry of lower-cost generic drugs and biosimilars;

and (ii) support the enactment of a public health insurance option.

Among other things, the Executive Order also directs HHS to provide a report on actions to combat excessive pricing of prescription drugs, enhance the domestic drug supply chain, reduce the price that the Federal government pays for drugs, and address price gouging in the industry;

and directs the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing regulations.

FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada.

On September 25, 2020, CMS stated drugs imported by states under this rule will not be eligible for federal rebates under Section 1927 of the Social Security Act and manufacturers would not report these drugs for “best price”

or Average Manufacturer Price purposes.

Since these drugs are not considered covered outpatient drugs, CMS further stated it will not publish a National Average Drug Acquisition Cost for these drugs.

If implemented, importation of drugs from Canada may materially and adversely affect the price we receive for any of our product candidates.

Further, on November 20, 2020 CMS issued an Interim Final Rule implementing the Most Favored Nation, or MFN, Model under which Medicare Part B reimbursement rates would have been calculated for certain drugs and biologicals based on the lowest price drug manufacturers receive in Organization for Economic Cooperation and Development countries with a similar gross domestic product per capita.

However, on August 6, 2021 CMS announced a proposed rule to rescind the Most Favored Nations rule.

Additionally, on November 30, 2020, HHS published a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.

Pursuant to court order, the removal and addition of the aforementioned safe harbors were delayed and recent legislation imposed a moratorium on implementation of the rule until January 1, 2026.

Congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

President Biden has issued multiple executive orders that have sought to reduce prescription drug costs.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.

The Inflation Reduction Act of 2022, or IRA, includes several provisions that will impact our business to varying degrees, including provisions that create a $2,000 out-of-pocket cap for Medicare Part D beneficiaries to $2,000 starting in 2025, impose new manufacturer financial liability on all drugs in Medicare Part D, allow the U.S.

government to negotiate Medicare Part B and Part D

pricing for certain high-cost drugs and biologics without generic or biosimilar competition, require companies to pay rebates to Medicare for drug prices that increase faster than inflation, and delay the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries.

Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one rare disease designation and for which the only approved indication is for that disease or condition.

If a product receives multiple rare disease designations or has multiple approved indications, it may not qualify for the orphan drug exemption.

The effect of IRA on our business and the healthcare industry in general is not yet known.

In addition, there have been several changes to the 340B drug pricing program, which imposes ceilings on prices that drug manufacturers can charge for medications sold to certain health care facilities.

On December 27, 2018, the District Court for the District of Columbia invalidated a reimbursement formula change under the 340B drug pricing program, and CMS subsequently altered the FYs 2019 and 2018 reimbursement formula on specified covered outpatient drugs (“SCODs”).

The court ruled this change was not an “adjustment”

3 unchanged sentences

On September 14, 2020, the plaintiffs-appellees filed a Petition for Rehearing En Banc (i.e., before the full court), but was denied on October 16, 2020.

Plaintiffs-appellees filed a petition for a writ of certiorari at the Supreme Court on February 10, 2021.

On Friday July 2, 2021, the Supreme Court granted the petition.

It is unclear how these developments could affect covered hospitals who might purchase our future products and affect the rates we may charge such facilities for our approved products in the future, if any.

Plaintiffs-appellees filed a petition for a writ of certiorari at the Supreme Court on February 10, 2021, and the petition was granted on July 2, 2021.

On June 15, 2022, the Supreme Court unanimously reversed the Court of Appeals' decision, holding that HHS's 2018 and 2019 reimbursement rates for 340B hospitals were contrary to the statute and unlawful.

Although a number of these, and other proposed measures will require authorization through additional legislation to become effective, Congress has indicated that it may continue to seek new legislative and/or administrative measures to control drug costs.

15 unchanged sentences

The transitory provisions of the new Clinical Trials Regulation offer sponsors the possibility to choose between the requirements of the previous Clinical Trials Directive and the Clinical Trials Regulation if the request for authorization of a clinical trial is submitted in the year after the new Clinical Trials Regulation became applicable.

If the sponsor chooses to submit under the Clinical Trials Directive, the clinical trial continues to be governed by the Directive until three years after the new Clinical Trials Regulation became applicable.

If the sponsor chooses to submit under the Clinical Trials Directive, the clinical trial continues to be governed by the Directive until three years after the new

Clinical Trials Regulation became applicable.

If a clinical trial continues for more than three years after the Clinical Trials Regulation became applicable, the Clinical Trials Regulation will at that time begin to apply to the clinical trial.

2 unchanged sentences

There are two types of marketing authorizations:

(1) the centralized authorization, which is issued by the European Commission through the centralized procedure based on the opinion of the Committee for Medicinal Products for Human Use (“CHMP”), a body of the EMA, and which is valid throughout the entire territory of the European Economic Area, or EEA (comprising the EU Member States plus Norway, Iceland and Liechtenstein);

(1) the centralized authorization, which is issued by the European Commission through the centralized procedure based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, a body of the EMA, and which is valid throughout the entire territory of the European Economic Area, or EEA (comprising the EU Member States plus Norway, Iceland and Liechtenstein);

and (2) national marketing authorizations, which is issued by the competent authorities of the Member States of the EU and only authorize marketing in that Member State’s national territory and not the EEA as a whole.

1 unchanged sentence

The centralized procedure is optional for products containing a new active substance not yet authorized in the EU, or for products that constitute a significant therapeutic, scientific, or technical innovation or which are in the interest of public health.

Gene therapy products are a type of advanced therapy medicinal product (“ATMP”) in the EU.

The scientific evaluation of marketing authorization applications for ATMPs is primarily performed by a specialized scientific committee called the Committee for Advanced Therapies (“CAT”).

Gene therapy products are a type of advanced therapy medicinal product, or ATMP, in the EU.

The scientific evaluation of marketing authorization applications for ATMPs is primarily performed by a specialized scientific committee called the Committee for Advanced Therapies, or CAT.

The CAT prepares a draft opinion on the quality, safety, and efficacy of the ATMP which is the subject of the marketing authorization application, which is sent for final approval to the CHMP.

9 unchanged sentences

If the product has not received a national marketing authorization in any Member State at the time of application, it can be approved simultaneously in various Member States through the decentralized procedure.

Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the Member States

in which an authorization is sought, one of which is selected by the applicant as the Reference Member State (“RMS”).

Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the Member States in which an authorization is sought, one of which is selected by the applicant as the Reference Member State, or RMS.

If the RMS proposes to authorize the product, and the other Member States do not raise objections, the product is granted a national marketing authorization in all the Member States where the authorization was sought.

12 unchanged sentences

The criteria for designating an orphan medicinal product in the EU, are similar in principle to those in the U.S.

Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated as orphan if the following criteria are fulfilled:

Under Article 3 of Regulation, or Regulation EC, 141/2000, a medicinal product may be designated as orphan if the following criteria are fulfilled:

(i) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition;

13 unchanged sentences

In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist.

The PRIority MEdicines (PRIME), scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation, where the marketing authorization application will be made through the centralized procedure.

The PRIority MEdicines, or PRIME, scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation, where the marketing authorization application will be made through the centralized procedure.

Eligible products must target conditions for which where is an unmet medical need, i.e., there is no satisfactory method of diagnosis, prevention or treatment in the EU or, if there is, the new medicine will bring a major therapeutic advantage) and they must show potential to benefit patients with unmet medical needs based on early clinical data.

2 unchanged sentences

Importantly, a dedicated contact and rapporteur from the EMA’s CHMP or Committee for Advanced Therapies are appointed early in PRIME scheme facilitating increased understanding of the product at the EMA’s committee level.

A kick-off meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.

A kick-off meeting initiates these relationships and includes a team of

multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.

Where, during the course of development, a medicine no longer meets the eligibility criteria, support under the PRIME scheme may be withdrawn.

Brexit and the Regulatory Framework in the United Kingdom

In June 2016, the electorate in the UK voted in favor of leaving the EU (commonly referred to as “Brexit”), and the UK formally left the EU on January 31, 2020.

In June 2016, the electorate in the UK voted in favor of leaving the EU, or commonly referred to as Brexit, and the UK formally left the EU on January 31, 2020.

There was a transition period during which EU pharmaceutical laws continued to apply to the UK, which expired on December 31, 2020.

4 unchanged sentences

For example, the UK has implemented the now repealed Clinical Trials Directive 2001/20/EC into national law through the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended).

The extent to which the regulation of clinical trials in the UK will mirror the new Clinical Trials Regulation now that has come into effect is not yet known, however the Medicines and Healthcare products Regulatory Agency (“MHRA”), the UK medicines regulator, has opened a consultation on a set of proposals designed to improve and strengthen the UK clinical trials legislation.

Such consultation is open until 14 March 2022.

The extent to which the regulation of clinical trials in the UK will mirror the new Clinical Trials Regulation now that has come into effect is not yet known, however the Medicines and Healthcare products Regulatory Agency, or MHRA, the UK medicines regulator, opened a consultation on a set of proposals designed to improve and strengthen the UK clinical trials legislation.

Such consultation was open until March 14, 2022.

The Foreign Corrupt Practices Act

12 unchanged sentences

Human Capital

As of March 4, 2022, we had 104 full-time employees and 1 part-time employee, 30 of whom have Ph.D.

As of February 28, 2023, we had 137 full-time employees and 1 part-time employee, 39 of whom have Ph.D.

Of these full-time employees, 105 employees are engaged in research and development activities and 32 are engaged in finance, business development and other general and administrative functions.

2 unchanged sentences

We recognize that attracting, motivating and retaining talent at all levels is vital to our continued success.

Our employees are a significant asset, and we aim to create an equitable, inclusive and empowering environment in which our employees can grow and advance their careers, with the overall goal of developing, expanding and retaining our workforce to support our current pipeline and future business goals.

Our employees are a significant asset, and we aim to create an equitable, inclusive and empowering environment in which our employees can grow and

advance their careers, with the overall goal of developing, expanding and retaining our workforce to support our current pipeline and future business goals.

By focusing on employee retention and engagement, we also improve our ability to support our clinical trials, our pipeline, our platform technologies, business and operations, and also protect the long-term interests of our securityholders.

7 unchanged sentences

We plan to continue to refine our efforts related to optimizing our use of human capital as we grow, including improvements in the way we hire, develop, motivate and retain employees.

Our facilities are located at two adjacent leased sites, both located at 830 Winter Street, Waltham, Massachusetts, 02451.

The first site consists of 25,472 square feet of office and laboratory space and is primarily used for research, clinical, manufacturing, and corporate activities.

Our lease expires September 30, 2024, with an option to extend three years.

The second site consists of 14,447 square feet of office and laboratory space and is primarily used for preclinical and clinical research.

Our lease on this facility expires on March 31, 2026.

On November 29, 2021, we entered into a lease agreement for an additional approximately 113,487 square feet of office and laboratory space located at 880 Winter Street, Waltham Massachusetts, 02451, which will serve as our headquarters.

The term of the lease will commence on the earlier of the date we commence our business operations at the location or when all improvements to the facility are completed and necessary occupancy permits are obtained.

The lease will have a term of approximately ten years and two months.

Our corporate headquarters is located at 830 Winter Street in Waltham, Massachusetts.

The facility at 830 Winter Street is 25,472 square feet of laboratory space, with a lease expiration of September 2024.

We also lease a facility at 880 Winter Street which is 113,487 square feet of office and laboratory space with a lease termination date of December 2032.

We believe that these facilities are adequate to meet our needs for the immediate future, and that, should it be needed, suitable additional space will be available to accommodate any such expansion of our operations.

16 unchanged sentences

Ri sk Factors.

Investing in our common stock involves a high degree of risk.

You should consider carefully the risks and uncertainties described below, together with all of the other information in this Annual Report, including the section entitled “Management’s Discussion and Analysis of Financial Condition and Results of Operations”

and our consolidated financial statements and the accompanying notes included elsewhere in this Annual Report and in our final prospectus for our IPO.

The risks and uncertainties described below are not the only ones we face.

Additional risks and uncertainties that we are unaware of or that we deem immaterial may also become important factors that adversely affect our business.

If any of the following risks actually occur, our business, financial condition, liquidity, operating results, and prospects could be materially and adversely affected.

RISK FACTOR SUMMARY

Our business operations are subject to numerous risks that, if realized, could materially and adversely affect our business, financial condition, results of operations, and future growth prospects.

These risks include, but are not limited to, the following:

Risks Related to Our Business and Industry

Our business depends upon the success of our proprietary platform.

Our limited operating history may make it difficult to evaluate the success of our business.

We have incurred significant losses since inception, and we expect to incur losses over the next several years and may not be able to achieve or sustain revenues or profitability in the future.

We have never generated, and may never generate, any revenue from sales of cell therapy products.

We will need to obtain substantial additional funding to complete the development and any commercialization of our product candidates, if approved.

Raising additional capital may cause dilution to our existing stockholders, restrict our operations or require us to relinquish rights to our intellectual property or product candidates on unfavorable terms.

Global economic uncertainty and financial market volatility caused by political instability, changes in international trade relationships and conflicts, such as the conflict between Russia and Ukraine, could make it more difficult for us to access financing and could adversely affect our business and operations.

Risks Related to the Development of Our Product Candidates

Our approach to the discovery and development of product candidates based on our proprietary platform represents a novel approach to cancer treatment, which creates significant challenges for us.

If we are unable to advance our product candidates through clinical development, obtain regulatory approval and ultimately commercialize our product candidates, or experience significant delays in doing so, our business will be materially harmed.

Although many of our personnel have extensive experience in clinical development and manufacturing at other companies, we have no direct experience as a company in conducting clinical trials or managing a manufacturing facility for our product candidates.

Our preclinical studies and clinical trials may fail to demonstrate adequately the safety, potency and purity of any of our product candidates, which would prevent or delay development, regulatory approval and commercialization.

Our business could be adversely affected by the effects of health epidemics, including the evolving effects of the COVID-19 pandemic and responses thereto.

We may rely on third parties to manufacture our clinical product supplies, and we may rely on third parties to produce and process our product candidates, if licensed.

Allogeneic hematopoietic stem cell transplantation is a high-risk procedure with curative potential that may result in complications or adverse events for patients in our clinical trials or for patients that use any of our product candidates, if approved.

Our product candidates may cause undesirable side effects or have other properties that could halt their clinical development, prevent their regulatory approval, require expansion of the trial size, limit their commercial potential, or result in significant negative consequences.

If we encounter difficulties enrolling patients in our clinical trials, our clinical development activities could be delayed or otherwise adversely affected.

The market opportunities for our product candidates may be relatively small and our estimates of the prevalence of our target patient populations may be inaccurate.

We face significant competition, and our operating results will suffer if we fail to compete effectively.

Risks Related to Manufacturing

Manufacturing and administering our product candidates is complex and we may encounter difficulties in production.

We plan to expand our existing manufacturing facility and infrastructure in lieu of relying on third parties for the manufacture of our product candidates for certain clinical purposes, which will be costly and time-consuming and may not be successful.

We may have difficulty validating our manufacturing process as we manufacture TCR-T therapy candidates from an increasingly diverse patient population for our clinical trials.

Risks Related to Government Regulation

The FDA regulatory approval process is lengthy and time-consuming, and we may experience significant delays in the clinical development and regulatory approval of our product candidates.

We may be unable to obtain regulatory approval for our product candidates under applicable regulatory requirements.

Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining regulatory approval of our product candidates in other jurisdictions.

Recently enacted and future legislation may increase the difficulty and cost for us to obtain marketing approval for and commercialize our product candidates and affect the prices we may obtain.

Risks Related to Our Intellectual Property

If we are unable to obtain and maintain patent protection for any product candidates we develop and for our technology, or if the scope of the patent protection obtained is not sufficiently broad, our competitors could develop and commercialize products, product candidates and technology similar or identical to ours, and our ability to successfully commercialize any product candidates we may develop may be adversely affected.

We are currently, and expect in the future to be, party to material license or collaboration agreements.

Third party claims of intellectual property infringement, misappropriation or other violations may prevent or delay our product discovery and development efforts.

Risks Related to Our Reliance on Third Parties

If the third parties we plan to rely on to conduct our clinical trials do not properly and successfully carry out their contractual duties or meet expected deadlines, we may not be able to obtain regulatory approval for or commercialize our product candidates.

We may not realize the benefits of our current or future collaborations, alliances, or licensing arrangements.

Our business involves a high degree of risk.

You should carefully consider the material and other risks and uncertainties described and summarized below, as well as the other information in this Annual Report on Form 10-K, including our consolidated financial statements and related notes and the section titled “Management’s Discussion and Analysis of Financial Condition and Results of Operations”

and “Special Note Regarding Forward-Looking Statements,”

as well as our other filings with the SEC, before you make an investment decision.

Our actual results could differ materially from those anticipated in the forward-looking statements as a result of factors that are described below and elsewhere in this Annual Report on Form 10-K.

The risks described below are not the only risks that we face.

The occurrence of any of the events or developments described below could materially and adversely affect our business, financial condition, results of operations and prospects.

As a result, the market price of our common stock could decline, and you may lose all or part of your investment in our common stock.

Risks Related to Our Business and Industry

1 unchanged sentence

Investment in biopharmaceutical product development is a highly speculative undertaking and entails substantial upfront capital expenditures and significant risk that any potential product candidate will fail to demonstrate adequate efficacy or an acceptable safety profile, gain regulatory approval and become commercially viable.

We are still in the early stages of development of our product candidates and have not yet initiated our first clinical trial.

We are still in the early stages of development of our product candidates and have only recently initiated clinical studies for TSC-100 and TSC-101.

We have no products licensed for commercial sale and have not generated any revenue from product sales to date, and we continue to incur significant research and development and other expenses related to our ongoing operations.

We have financed our operations primarily through private placements of our preferred stock.

We have financed our operations primarily through private placements of our preferred stock, our initial public offering in 2021 and borrowings under a secured loan agreement in September 2022.

We have incurred significant net losses in each period since our inception in April 2018.

2 unchanged sentences

We expect to continue to incur significant losses for the foreseeable future, and we expect these losses to increase substantially if and as we:

continue our research and development efforts to identify and develop lead product candidates and submit investigational new drug applications, or INDs, for such lead product candidates;

continue our research and development efforts to identify and develop lead product candidates and submit additional investigational new drug applications, or INDs, for such lead product candidates;

conduct preclinical studies and commence clinical trials for our current and future product candidates based on our proprietary platform;

develop processes suitable for manufacturing and clinical development

continue to develop and then expand our manufacturing capabilities;

seek marketing approvals for any product candidates that successfully complete clinical trials;

continue to develop and expand our manufacturing capabilities;

seek marketing approvals for any of our product candidates that successfully complete clinical trials;

build commercial infrastructure to support sales and marketing for our product candidates;

2 unchanged sentences

continue to operate as a public company.

Because of the numerous risks and uncertainties associated with biopharmaceutical product research and development, we are unable to accurately predict the timing or amount of increased expenses we will incur or when, if ever, we will be able to achieve profitability.

Even if we succeed in commercializing one or more of our product candidates, we will continue to incur substantial research and development and other expenditures to develop, seek regulatory approval for, and market additional product candidates.

Because of the numerous risks and uncertainties associated with biopharmaceutical product research and development, we are unable to accurately predict the timing or amount of the increased expenses we will incur or when, if ever, we will be able to achieve profitability.

Even if we succeed in commercializing one or more of our product candidates, we will continue to incur substantial research and development expenses and other expenditures to develop, seek regulatory approval for, and market additional product candidates.

We may encounter unforeseen expenses, difficulties, complications, delays and other unknown factors that may adversely affect our business.

3 unchanged sentences

Our business depends upon the success of our proprietary platform.

Our success depends on our ability to use our proprietary platform to discover the natural targets of clinically relevant TCRs through our TargetScan technology, to discover highly active TCRs for known targets through our ReceptorScan technology, to genetically engineer patient- or donor-derived T cells safely and reproducibly through our T-Integrate technology, to obtain regulatory approval for product candidates derived from our proprietary platform and related technologies, and to then commercialize our product candidates addressing one or more indications.

All of our product candidates will require significant additional clinical and non-clinical development, review and approval by the FDA or other regulatory authorities in one or more jurisdictions, substantial investment, access to sufficient commercial manufacturing capacity and significant marketing efforts before they can be successfully commercialized.

Our platform and our product candidates have not yet been evaluated in humans and may never become commercialized.

Our success depends on our ability to use our proprietary platform (i) to discover the natural targets of clinically relevant TCRs through our TargetScan technology, (ii) to discover highly active TCRs for known targets through our ReceptorScan technology, (iii) to genetically engineer patient- or donor-derived T cells safely and reproducibly through our T-Integrate technology, (iv) to obtain regulatory approval for product candidates derived from our proprietary platform and related technologies, and (v) to then commercialize our product candidates that address one or more indications.

All of our product candidates will require significant additional clinical and non-clinical development, review and approval by the U.S.

Food and Drug Administration, or FDA, or other regulatory authorities in one or more jurisdictions, substantial investment, access to sufficient commercial manufacturing capacity and significant marketing efforts before they can be successfully commercialized.

Our proprietary platform and our product candidates have not yet been evaluated in humans and may never become commercialized.

Moreover, all of our current product candidates are being developed using our proprietary platform and leveraging the same or similar technology, manufacturing process and development program.

3 unchanged sentences

Our limited operating history may make it difficult to evaluate the success of our business to date and to assess our future viability.

We are a preclinical-stage immunotherapy company with a limited operating history.

We commenced operations in April 2018, and our operations to date have been limited to organizing and staffing our company, business planning, raising capital, conducting discovery and research activities, filing patent applications, identifying potential product candidates, undertaking preclinical studies, entering into collaborations, establishing manufacturing for initial quantities of our product candidates, and establishing arrangements for component materials for such manufacturing.

All of our product candidates are still in preclinical development.

We have not yet demonstrated our ability to successfully initiate, conduct or complete any clinical trials, obtain marketing approvals, manufacture clinical or commercial-scale product or arrange for a third party to do so on our behalf, or conduct sales, marketing and distribution activities necessary for successful product commercialization.

We are a clinical-stage biopharmaceutical company with a limited operating history.

We commenced operations in April 2018, and our operations to date have been limited to organizing and staffing our company, business planning, raising capital, conducting discovery and research activities, filing patent applications, identifying potential product candidates, undertaking preclinical studies, entering into licenses and collaborations, establishing manufacturing for initial quantities of our product candidates, and establishing arrangements for component materials for such manufacturing.

Although we have initiated clinical trials for certain of our product candidates, we have not yet demonstrated our ability to successfully conduct or complete any clinical trials, obtain marketing approvals, manufacture clinical or commercial-scale product or arrange for a third party to do so on our behalf, or conduct sales, marketing and distribution activities necessary for successful product commercialization.

Consequently, any predictions about our future success or viability may not be as accurate as they could be if we had a longer operating history.

8 unchanged sentences

We do not expect to generate significant revenue unless or until we successfully complete clinical development and obtain regulatory approval of, and then successfully commercialize, at least one of our product candidates.

All of our product candidates are in the preclinical stages of development and will require additional preclinical studies, process development, clinical development, regulatory review and approval, substantial investment, access to sufficient commercial manufacturing capacity and significant marketing efforts before we can generate any revenue from product sales.

None of our product candidates have completed IND-enabling studies.

TSC-100, one of our lead product candidates targeting HA-1, an epitope present on leukemia cells, is in the early stages of development and has not yet been evaluated in clinical trials and will require additional regulatory review and approval, substantial investment, access to sufficient commercial manufacturing capacity and significant marketing efforts before we can generate any revenue from product sales.

Although we have initiated clinical trials for certain of our product candidates, we have not yet demonstrated an ability to successfully complete clinical trials of our product candidates, obtain marketing approvals, manufacture a commercial-scale medicine, or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful commercialization to enable us to generate any revenue from product sales.

Our other product candidates are in early preclinical stages.

1 unchanged sentence

Our ability to generate revenue depends on a number of factors, including, but not limited to:

our ability to develop processes suitable for clinical manufacturing and to obtain related CMC regulatory approvals;

our ability to develop processes suitable for clinical manufacturing and to obtain related chemistry, manufacturing, and controls, or CMC, regulatory approvals;

timely completion of our preclinical studies and clinical trials, which may be significantly slower or cost more than we currently anticipate and will depend substantially upon the performance of third party contractors;

our ability to complete IND-enabling studies and successfully submit INDs or comparable applications;

our ability to continue to complete IND-enabling studies and to continue to successfully submit INDs or comparable applications;

whether we are required by the U.S.

1 unchanged sentence

our ability to demonstrate to the satisfaction of the FDA and similar foreign regulatory authorities the safety, potency, purity and acceptable risk to benefit profile of our product candidates or any future product candidates;

the prevalence, duration and severity of potential side effects or other safety issues experienced with our product candidates or future product candidates, if any;

the prevalence, duration and severity of potential side effects or other safety issues, including adverse events, experienced with our product candidates or future product candidates, if any;

the timely receipt of necessary marketing approvals from the FDA and similar foreign regulatory authorities;

the willingness of physicians, operators of clinics and patients to utilize or adopt any of product candidates or future product candidates to treat liquid or solid tumors;

our ability and the ability of third parties with whom we contract to manufacture adequate clinical and commercial supplies of our product candidates or any future product candidates, remain in good standing with regulatory authorities and develop, validate and maintain commercially viable manufacturing processes that are compliant with current good manufacturing practices (cGMP);

the willingness of physicians, operators of clinics and patients to utilize or adopt any of product candidates or future product candidates to treat hematologic malignancies or solid tumors;

our ability and the ability of our third parties contractors to manufacture adequate clinical and commercial supplies of our product candidates or any future product candidates, remain in good standing with regulatory authorities and develop, validate and maintain commercially viable manufacturing processes that are compliant with current good manufacturing practices, or cGMP;

our ability to successfully develop a commercial strategy and thereafter commercialize our product candidates or any future product candidates in the United States and internationally, if licensed for marketing, reimbursement, sale and distribution in such countries and territories, whether alone or in collaboration with others;

1 unchanged sentence

our ability to establish, obtain, maintain, protect and enforce intellectual property and proprietary rights in and to our product candidates or any future product candidates.

Many of the factors listed above are beyond our control, and could cause us to experience significant delays or prevent us from obtaining regulatory approvals or commercialize our product candidates.

Many of the factors listed above are beyond our control, and could cause us to experience significant delays or prevent us from obtaining regulatory approvals or commercializing our product candidates.

Even if we are able to commercialize our product candidates, we may not achieve profitability soon after generating product sales, if ever.

2 unchanged sentences

If we are unable to raise this necessary capital when needed, we would be forced to delay, reduce or eliminate our product development programs, commercialization efforts or other operations.

Since our inception, we have financed our operations through private placements of preferred stock and through our initial public offering.

Since our inception, we have financed our operations through private placements of preferred stock;

through our initial public offering;

and through our debt financing facility.

The development of biopharmaceutical product candidates is capital intensive and we expect our expenses to increase substantially during the next few years.

3 unchanged sentences

As of December 31, 2022, we had $120.0 million in cash and cash equivalents.

Based on our current operating plan, we believe that our existing cash and cash equivalents will be sufficient to fund our operating expenses and capital expenditure requirements into 2024.

Based on our current operating plan, we believe that our existing cash and cash equivalents will be sufficient to fund our operating expenses and capital expenditure requirements into the second quarter of 2024.

Accordingly, our existing cash and cash equivalents will not be sufficient for us to fund any of our product candidates through regulatory approval, and we will need to raise substantial additional capital to complete the development and commercialization of our product candidates through equity offerings, debt financings, marketing and distribution arrangements and other collaborations, strategic alliances and licensing arrangements or other sources.

31 unchanged sentences

If we are unable to raise additional funds through equity or debt financing or through collaborations, licensing arrangements or strategic partnerships when needed, we may be required to delay, limit, reduce or terminate our product development or commercialization efforts.

Global economic uncertainty and financial market volatility caused by political instability, changes in international trade relationships and conflicts, such as the ongoing conflict between Russia and Ukraine, could make it more difficult for us to access financing and could adversely affect our business and operations.

Our ability to raise capital is subject to the risk of adverse changes in the market value of our stock.

Periods of macroeconomic weakness or recession and heightened market volatility caused by adverse geopolitical developments could increase these risks, potentially resulting in adverse impacts on our ability to raise further capital on favorable terms.

The impact of geopolitical tension, such as a deterioration in the bilateral relationship between the US and China or an escalation in conflict between Russia and Ukraine, including any resulting sanctions, export controls or other restrictive actions that may be imposed by the US and/or other countries against governmental or other entities in, for example, Russia, also could lead to disruption, instability and volatility in global trade patterns, which may in turn impact our ability to source necessary reagents, raw materials and other inputs for our research and development operations.

The impact of geopolitical tension, such as a deterioration in the bilateral relationship between the US and China or in the ongoing conflict between Russia and Ukraine, including resulting sanctions, export controls or other restrictive actions that may be imposed by the US and/or other countries against governmental or other entities in, for example, Russia, also could lead to disruption, instability and volatility in global trade patterns, which may in turn impact our ability to source necessary reagents, raw materials and other inputs for our research and development operations.

Any of the abovementioned factors could affect our business, prospects, financial condition, and operating results.

The extent and duration of any political instability and resulting market disruptions are impossible to predict, but could be substantial.

Any such disruptions may also have the effect of heightening many of the other risks and uncertainties described elsewhere in this “Risk Factors”

Recent volatility in capital markets and lower market prices for many securities may affect our ability to access new capital through sales of shares of our common stock or issuance of indebtedness, which may harm our liquidity, limit our ability to grow our business, pursue acquisitions or improve our operating infrastructure and restrict our ability to compete in our markets.

Our operations consume substantial amounts of cash, and we intend to continue to make significant investments to support our business growth, respond to business challenges or opportunities, develop new products, retain or expand our current levels of personnel, support our programs, enhance our operating infrastructure, and potentially acquire complementary businesses and technologies.

Our future capital requirements may be significantly different from our current estimates and will depend on many factors, including the need to:

finance unanticipated working capital requirements, including clinical manufacturing capacity;

support our discovery and preclinical development activities, and clinical trials for our product candidates;

pursue acquisitions or other strategic relationships;

respond to competitive pressures.

Accordingly, we may need to pursue equity or debt financings to meet our capital needs.

With uncertainty in the capital markets and other factors, such financing may not be available on terms favorable to us or at all.

If we raise additional funds through further issuances of equity or convertible debt securities, our existing stockholders could suffer significant dilution, and any new equity securities we issue could have rights, preferences, and privileges superior to those of holders of our common stock.

Any debt financing secured by us in the future could involve additional restrictive covenants relating to our capital-raising activities and other financial and operational matters, which may make it more difficult for us to obtain additional capital and to pursue business opportunities, including potential acquisitions.

If we are unable to obtain adequate financing or financing on terms satisfactory to us, we could face significant limitations on our ability to invest in our operations and otherwise suffer harm to our business.

The terms of our loan agreement place restrictions on our operating and financial flexibility.

If we raise additional capital through debt financing, the terms of any new debt could further restrict our operating and financial flexibility.

On September 9, 2022, we entered into a Loan and Security Agreement with K2HV (the Loan Agreement) pursuant to which K2HV may provide us with convertible term loans in an aggregate principal amount of up to $60 million, of which $30 million was fully funded at the closing date in September 2022, $10 million will be funded in the second tranche upon the achievement of certain financial and clinical milestones and $20 million may be funded in the third tranche at K2HV’s discretion.

Our obligations under the Loan Agreement are secured by a security interest in substantially all of our assets (other than intellectual property), subject to certain exceptions, and will be guaranteed by each of the Company’s future direct or indirect subsidiaries, subject to certain exceptions.

In addition, during the term of the Loan Agreement, we must maintain minimum unrestricted cash and cash equivalents equal to 5.0 times

the average cash burn measured over the trailing three-month period.

The Loan Agreement contains customary representations and warranties, and also includes customary events of default, including payment default, breach of covenants, change of control, and material adverse effects.

The Loan Agreement restricts certain activities, such as disposing of the Company’s business or certain assets, incurring additional debt or liens or making payments on other debt, making certain investments and declaring dividends, acquiring or merging with another entity, engaging in transactions with affiliates or encumbering intellectual property, among others.

Upon the occurrence of an event of default, a default interest rate of an additional 5% per annum may be applied to the outstanding loan balances, and K2HV may declare all outstanding obligations immediately due and payable and exercise all of its rights and remedies as set forth in the Loan Agreement and under applicable law.

Any declaration by K2HV of an event of default could significantly harm our business and prospects and could cause the price of our common stock to decline.

We may not have enough available cash or be able to raise additional funds through equity or debt financings to repay these outstanding obligations at the time any event of default occurs.

Further, if we raise any additional capital through debt financing, the terms of such additional debt could further restrict our operating and financial flexibility.

Risks Related to the Development of Our Product Candidates

Our approach to the discovery and development of product candidates based on our proprietary platform represents a novel approach to cancer treatment, which creates significant challenges for us.

Our future success depends on the successful development of our product candidates, which target liquid and solid tumors utilizing T-cell receptor therapies, or TCR-T therapies.

Our future success depends on the successful development of our product candidates, which target hematologic malignancies and solid tumors utilizing T cell receptor therapies, or TCR-T therapies.

Advancing our product candidates creates significant challenges for us, including:

educating medical personnel about the administration of TCR-T therapies on a stand-alone basis or in combination with built-in immune and tumor modulators;

while no such side effects have been observed to date in any of our preclinical studies, educating medical personnel regarding the potential side effect profile of our product candidates, such as the potential adverse side effects related to cytokine release syndrome (CRS), graft vs.

while no such side effects have been observed to date in any of our preclinical or clinical studies, educating medical personnel regarding the potential side effect profile of our product candidates, such as the potential adverse side effects related to cytokine release syndrome (CRS), graft vs.

host disease, neurotoxicity or autoimmune or rheumatologic disorders, which are the most common adverse side effects associated with engineered T cell therapies;

2 unchanged sentences

manufacturing TCR-Ts efficiently and consistently without the use of viral vectors using our T-Integrate technology;

developing a complete shipment lifecycle and supply chain, including efficiently managing shipment of patient cells from and to clinical sites, minimizing potential contamination to the cell product and effectively scaling manufacturing capacity to meet demand;

developing a complete shipment lifecycle and supply chain, including efficiently managing the shipment of patient cells from and to clinical sites, minimizing potential contamination to the cell product and effectively scaling manufacturing capacity to meet demand;

developing processes suitable for clinical manufacturing and obtaining related CMC regulatory approvals;

1 unchanged sentence

using medicines to manage adverse side effects of our product candidates, which may not adequately control the side effects and/or may have a detrimental impact on the potency of the treatment;

obtaining and maintaining regulatory approval from the FDA for our product candidates;

obtaining and maintaining regulatory approval from the FDA or comparable foreign regulatory authority for our product candidates;

establishing sales and marketing capabilities upon obtaining any regulatory approval to gain market acceptance of a novel therapy.

In developing our product candidates, we have not exhaustively explored different options in the design of the TCR construct and in the method for manufacturing TCR-T therapies.

We may find our existing TCR-T therapy candidates and manufacturing process may be substantially improved with future design or process changes, necessitating development of new or additional TCR constructs and further clinical testing and delaying commercial launch of our first products.

We may find that our existing TCR-T therapy candidates and manufacturing process may be substantially improved with future design or process changes, necessitating development of new or additional TCR constructs and further clinical testing, which may delay the commercial launch of our first products.

We have made several TCR constructs and used preclinical studies to select product candidates to advance into clinical trials.

5 unchanged sentences

We are very early in our development efforts.

All of our product candidates are still in preclinical development.

We are very early in our development efforts.

All of our product candidates are still in preclinical development, with TSC-100, our most advanced product candidate, still in preclinical development and not having completed IND-enabling studies.

Our ability to generate product revenues, which we do not expect will occur for many years, if ever, will depend significantly on the successful

development and eventual commercialization of one or more of our product candidates.

We have only recently cleared the INDs for TSC-100 and TSC-101, our most advanced product candidates as well as for T-Plex, TSC-204-A0201 and TSC-204-C0702.

Our other product candidates are still in preclinical development.

Our ability to generate product revenues, which we do not expect will occur for many years, if ever, will depend significantly on the successful development and eventual commercialization of one or more of our product candidates.

The success of our product candidates will depend on several factors, including the following:

5 unchanged sentences

obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our product candidates;

making arrangements with third party manufacturers, or establishing manufacturing capabilities, for both clinical and commercial supplies of our product candidates;

making arrangements with third party manufacturers, or expanding our manufacturing capabilities, for both clinical and commercial supplies of our product candidates;

establishing sales, marketing and distribution capabilities and launching commercial sales of our product candidates, if and when approved, whether alone or in collaboration with others;

5 unchanged sentences

If we do not achieve one or more of these factors in a timely manner or at all, we could experience significant delays or be unable to successfully commercialize our product candidates, which would materially harm our business.

Although many of our personnel have extensive experience in clinical development and manufacturing at other companies, we have no direct experience as a company in conducting clinical trials and little direct experience managing a manufacturing facility for our product candidates.

In part because of this lack of experience, we cannot be certain that our ongoing preclinical studies will be completed on time or if the planned preclinical studies and clinical trials will begin or be completed on time, if at all.

Although many of our personnel have extensive experience in clinical development and manufacturing at other companies, we have limited experience as a company in conducting clinical trials and little direct experience managing a manufacturing facility for our product candidates.

In part because of this lack of experience, we cannot be certain that our ongoing preclinical studies will be completed on time or if the planned preclinical and clinical trials studies and clinical trials will begin or be completed on time, if at all.

Large-scale clinical trials would require significant additional financial and management resources and reliance on third party clinical investigators, contract research organizations (CROs) and consultants.

Relying on third party clinical investigators, CROs and consultants may force us to encounter delays that are outside of our control.

We currently intend to further expand our existing cell manufacturing facility for Phase 1 and Phase 2 clinical trials, which will require significant resources, and we have limited direct experience as a company in expanding or managing a manufacturing facility.

In part because of this lack of experience, we cannot be certain that the further expansion of our existing manufacturing facility will be completed on time, if at all, or if the planned clinical trials will begin or be completed on time, if at all.

Although we have recently expanded our existing cell manufacturing facility for Phase 1 and Phase 2 clinical trials, we have limited direct experience as a company in expanding or managing a manufacturing facility.

In part because of this lack of experience, we cannot be certain that any further expansion of our existing manufacturing facility will be completed on time, if at all, or if the planned clinical trials will begin or be completed on time, if at all.

In part because of our inexperience, we may have unacceptable or inconsistent product quality success rates and yields, and we may be unable to maintain adequate quality control, quality assurance and qualified personnel.

In addition, if we switch from manufacturing in our own facility to manufacturing in a different facility (for example, at an external contract manufacturing organization) for one or more of our product candidates in the future or make changes to our manufacturing process, we may need to conduct additional preclinical studies to bridge our modified product candidates to earlier versions.

In addition, if we switch from manufacturing in our own facility to manufacturing in a different facility (for example, at an external contract manufacturing organization, or CMO) for one or more of our product candidates in the future or make changes to our manufacturing process, we may need to conduct additional preclinical studies to bridge our modified product candidates to earlier versions.

Failure to successfully further expand our existing manufacturing facility could adversely affect our process and clinical development timelines, regulatory approvals, and the commercial viability of our product candidates.

Our business is highly dependent on our current product candidates and we must complete IND-enabling studies and clinical testing before we can seek regulatory approval and begin commercialization of any of our product candidates.

There is no guarantee that any of our product candidates will proceed in preclinical or clinical development or achieve regulatory approval.

There is no guarantee that any of our product candidates will proceed through preclinical or clinical development or achieve regulatory approval.

The process for obtaining marketing approval for any product candidate is very long and risky and there will be significant challenges for us to address in order to obtain marketing approval as planned or, if at all.

There is no guarantee that the results obtained in current preclinical studies or our planned IND-enabling studies of TSC-100, TSC-101, TSC-102, TSC-200, TSC-201, TSC-202, and TSC-203 will be sufficient to obtain regulatory approval or marketing authorization for such product candidates.

There is no guarantee that the results obtained in current preclinical studies or our planned IND-enabling studies of our current or future product candidates will be sufficient to obtain regulatory approval or marketing authorization for such product candidates.

Negative results in the development of our lead product candidates may also impact our ability to obtain regulatory approval for our other product candidates, either at all or within anticipated timeframes because, although other product candidates may target different indications, the underlying proprietary platform, manufacturing process and development process is the same for all of our product candidates.

Accordingly, a failure in any one program may affect the ability to obtain regulatory approval to continue or conduct clinical programs for other product candidates.

Accordingly, a failure in any one of our programs may affect the ability to obtain regulatory approval to continue or conduct clinical programs for other product candidates.

In addition, because we have limited financial and personnel resources and are placing significant focus on the development of our lead product candidates, we may forgo or delay pursuit of opportunities with other future product candidates that later prove to have greater commercial potential.

1 unchanged sentence

Our spending on current and future research and development programs and other future product candidates for specific indications may not yield any commercially viable future product candidates.

If we do not accurately evaluate the commercial potential or target market for a particular future product candidate, we may relinquish valuable rights to those future product candidates through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such future product candidates.

If we do not accurately evaluate the commercial potential or target market for a particular future product candidate, we may relinquish valuable rights to those future product candidates through collaborations, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such future product candidates.

12 unchanged sentences

If our preclinical studies and clinical trials are not sufficient to support regulatory approval of any of our product candidates, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development of such product candidate.

We cannot be certain that our preclinical study and clinical trial results will be sufficient to support regulatory approval of our product candidates.

We cannot be certain that our ongoing and future preclinical study and clinical trial results will be sufficient to support regulatory approval of our product candidates.

Clinical testing is expensive and can take many years to complete, and its outcome is inherently uncertain.

2 unchanged sentences

We may experience delays in obtaining the FDA’s authorization to initiate clinical trials under future INDs, completing ongoing preclinical studies of our other product candidates, and initiating our planned preclinical studies and clinical trials.

Additionally, we cannot be certain that preclinical studies or clinical trials for our product candidates will begin on time, not require redesign, enroll an

adequate number of subjects on time, or be completed on schedule, if at all.

Additionally, we cannot be certain that preclinical studies or clinical trials for our product candidates will begin on time, not require redesign, enroll an adequate number of subjects on time, or be completed on schedule, if at all.

Clinical trials can be delayed or terminated for a variety of reasons, including delays or failures related to:

2 unchanged sentences

reaching agreement on acceptable terms with prospective CROs and clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and clinical trial sites;

obtaining institutional review board (IRB) approval at each clinical trial site;

obtaining institutional review board, or IRB, approval at each clinical trial site;

recruiting or retaining an adequate number of suitable patients to participate in a clinical trial, including as a result of actions taken by governments and individuals in response to the COVID-19 pandemic;

having subjects complete a clinical trial or return for post-treatment follow-up;

clinical trial sites deviating from clinical trial protocol or dropping out of a clinical trial;

clinical trial sites deviating from the approved clinical trial protocol or dropping out of a clinical trial;

addressing subject safety concerns that arise during the course of a clinical trial;

8 unchanged sentences

the cost of clinical trials of our product candidates may be greater than we anticipate;

the effects of the ongoing COVID-19 global pandemic;

the effects of the ongoing COVID-19 pandemic;

the quality of our product candidates or other materials necessary to conduct preclinical studies or clinical trials of our product candidates may be insufficient or inadequate;

3 unchanged sentences

Accordingly, our clinical trial costs are likely to be significantly higher than those for more conventional therapeutic technologies or drug product candidates.

We could also encounter delays if a clinical trial is suspended or terminated by us, by the IRBs of the institutions in which such clinical trials are being conducted, by the Data Safety Monitoring Board (DSMB) for such clinical trial or by the FDA or other regulatory authorities.

Such authorities may suspend or terminate a clinical trial due to a number of factors, including failure to conduct the clinical

trial in accordance with regulatory requirements or our clinical trial protocols, inspection of the clinical trial operations or trial site by the FDA or other regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from the product candidates, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial.

We could also encounter delays if a clinical trial is suspended or terminated by us, by the IRBs of the institutions in which such clinical trials are being conducted, by the data safety monitoring board for such clinical trial or by the FDA or other regulatory authorities.

Such authorities may suspend or terminate a clinical trial due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical trial protocols, inspection of the clinical trial operations or trial site by the FDA or other regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from the product candidates, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial.

If we experience delays in the completion, or termination, of any preclinical study or clinical trial of our product candidates, the commercial prospects of our product candidates may be harmed, and our ability to generate revenues from any of these product candidates will be delayed or not realized at all.

3 unchanged sentences

Our business could be adversely affected by the effects of health epidemics, including the evolving effects of the COVID-19 pandemic, in regions where we, our partners or other third parties on which we rely have significant manufacturing facilities, concentrations of potential clinical trial sites or other business operations.

The COVID-19 pandemic has had and may continue have a material effect on our operations as well as the business or operations of our partners or other third parties with whom we or our partners conduct business.

Health epidemics in regions where we have concentrations of potential clinical trial sites or other business operations could adversely affect our business, including by causing significant disruption in the operations of third parties upon whom we rely.

For example, the COVID-19 pandemic has presented a substantial public health and economic challenge around the world and is affecting employees, patients, communities and business operations, as well as the U.S.

Public health crises such as pandemics or similar outbreaks could adversely impact our business.

In late 2019, a novel strain of a virus named SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), or coronavirus, which causes COVID-19, emerged in Wuhan, China and has reached most countries across the world, including all 50 states within the U.S., and including Waltham, Massachusetts, where our primary office and laboratory space is located.

The coronavirus pandemic continues to evolve, with new variants of the SARS-CoV-2 virus identified, and has led to the implementation of various responses, including government-imposed quarantines, travel restrictions, mask and vaccine mandates and other public health safety measures.

The extent to which COVID-19 impacts our operations or those of our third party partners, including our preclinical studies or clinical trial operations, will depend on future developments, which are highly uncertain and cannot be predicted with confidence, including the duration of the outbreak, new information that will emerge concerning the variants of the coronavirus and the actions to contain the coronavirus or treat its impact, among others.

The continued spread of COVID-19 globally and the continued identification of new variants of the SARS-CoV-2 virus could adversely impact our preclinical or clinical trial operations in the U.S., including our ability to recruit and retain patients and principal investigators and site staff who, as healthcare providers, may have heightened exposure to COVID-19 if an outbreak occurs in their geography.

For example, similar to other biopharmaceutical companies, we may experience delays in initiating IND-enabling studies, protocol deviations, enrolling our clinical trials, or dosing of patients in our clinical trials as well as in activating new trial sites.

COVID-19 may also affect employees of third-party CROs located in affected geographies that we rely upon to carry out our clinical trials.

In addition, as a result of medical complications associated with microsatellite stable colorectal cancer, or MSS CRC, the patient populations that our most advanced and other product candidates target may be particularly susceptible to COVID-19, which may make it more difficult for us to identify patients able to enroll in our current and future clinical trials and may impact the ability of enrolled patients to complete any such trials.

Any negative impact COVID-19 has to patient enrollment or treatment or the execution of our product candidates could cause costly delays to our clinical trial activities, which could adversely affect our ability to obtain regulatory approval for and to commercialize our product candidates, increase our operating expenses, and have a material adverse effect on our financial results.

The adverse impact of public health crises such as pandemics or similar outbreaks in the countries and regions where we have concentrations of potential clinical trial sites or other business operations and where several of our third party suppliers and contractors are located could adversely affect our business, including by causing significant disruption in the operations of third parties upon whom we rely.

The COVID-19 pandemic has presented and continues to present a substantial public health and economic challenge around

the world and is affecting employees, patients, communities and business operations, as well as the U.S.

economy and financial markets.

Our headquarters is located in the Greater Boston Area.

In addition, several of our third party suppliers and contractors are located in countries and regions that have been negatively impacted by the COVID-19 global pandemic.

In March 2020, the U.S.

government imposed bans and restrictions on travel between the United States, Asia and certain other continents and countries and other countries have restricted travel to and from the United States.

Although, the Commonwealth of Massachusetts has permitted businesses to re-open on a limited basis, we have implemented work-from-home policies for a vast majority of our employees.

While we have implemented what we believe to be a reasonable protocol to ensure the safety and wellbeing of employees returning to the office, these measures may not be sufficient to mitigate the risks posed by the virus or otherwise be satisfactory to government authorities.

The effects of our work-from-home policies may negatively impact productivity, disrupt our business and delay our clinical programs and timelines, the magnitude of which will depend, in part, on the length and severity of any current or future restrictions and other limitations on our ability to conduct our business in the ordinary course.

While the Company has implemented what it believes to be a reasonable protocol to ensure the safety and wellbeing of employees returning to the office, these measures may not be sufficient to mitigate the risks posed by the virus or otherwise be satisfactory to government authorities.

The effects of our policies may negatively impact productivity, disrupt our business and delay our clinical programs and timelines, the magnitude of which will depend, in part, on the length and severity of any current or future restrictions and other limitations on our ability to conduct our business in the ordinary course.

In connection with these measures, we may be subject to claims based upon, arising out of or related to COVID-19 and our actions and responses thereto, including any determinations that we may make to continue to operate or to re-open our facilities where permitted by applicable law.

These and similar, and perhaps more severe, disruptions in our operations could negatively impact our business, financial condition, results of operations and growth prospects.

In addition, our planned clinical trials may be affected by the COVID-19 outbreak.

Site initiation and patient enrollment may be delayed due to prioritization of hospital resources toward the COVID-19 outbreak.

The COVID-19 pandemic might also affect our planned clinical trials.

Site initiation and patient enrollment may be delayed due to prioritization of hospital resources toward the COVID-19 pandemic.

Some patients may not be able to comply with clinical trial protocols if quarantines impede patient movement or interrupt healthcare services.

Similarly, our ability to recruit and retain patients and principal investigators and site staff who, as healthcare providers, may have heightened exposure to COVID-19 and adversely impact our planned clinical trial operations.

Furthermore, while the potential economic impact brought by, and the duration of, the COVID-19 pandemic may be difficult to assess or predict, the pandemic could result in significant and prolonged disruption of global financial markets, reducing our ability to access capital, which could in the future negatively affect our liquidity.

In addition, since the beginning of the COVID-19 pandemic, several vaccines for COVID-19 have received Emergency Use Authorization by the FDA and a number of those later received marketing approval.

Additional vaccines may be authorized or approved in the future.

The resultant demand for vaccines and potential for manufacturing facilities and materials to be commandeered under the Defense Production Act of 1950, or equivalent foreign legislation, may make it more difficult to obtain materials or manufacturing slots for the products needed for our clinical trials, which could lead to delays in these trials and/or issues with our commercial supply.

The potential economic impact brought by, and the duration of, the COVID-19 pandemic may be difficult to assess or predict, the pandemic could result in significant and prolonged disruption of global financial markets, reducing our ability to access capital, which could in the future negatively affect our liquidity.

In addition, a recession or market correction resulting from the spread of COVID-19 could materially affect our business and the value of our common stock.

While we expect the COVID-19 pandemic to continue to adversely affect our business operations, the extent of the impact on our development and regulatory efforts and the future value of and market for our common stock will depend on future developments that are highly uncertain and cannot be predicted with confidence at this time, such as the ultimate duration of the pandemic, travel restrictions, quarantines, social distancing and business closure requirements in the U.S.

While the COVID-19 pandemic may continue to adversely affect our business operations, the extent of the impact on our development and regulatory efforts and the future value of and market for our common stock will depend on future developments that are highly uncertain and cannot be predicted with confidence at this time, such as the ultimate duration of the pandemic, travel restrictions, quarantines, social distancing and business closure requirements in the U.S.

and in other countries, and the effectiveness of actions taken globally to contain and treat COVID-19.

1 unchanged sentence

We may rely on third parties to manufacture our clinical product supplies, and we may rely on third parties to produce and process our product candidates, if licensed.

We currently intend to establish facilities to manufacture our clinical scale product candidates for our Phase 1 and Phase 2 clinical trials for TSC-100, TSC-101, TSC-102, TSC-200, TSC-201, TSC-202, and TSC-203.

We have established facilities to manufacture our clinical scale product candidates for our Phase 1 and Phase 2 clinical trials of our current product candidates.

However, we rely on outside vendors to manufacture supplies for our manufacturing process, and we expect to rely on outside vendors to manufacture our product candidates for registration-enabling additional clinical trials as well as commercial sales.

1 unchanged sentence

We plan to make changes as we work to optimize the manufacturing process.

For example, we may switch or be required to switch from research-grade materials to commercial-grade materials in order to get regulatory approval of our product candidates, which could delay regulatory approval, if any.

We cannot be sure that even minor changes in the process will result in therapies that are safe and effective and licensed for commercial sale.

In addition, changes in the manufacturing process may result in the need to conduct additional bridging clinical trials to demonstrate product comparability.

The facilities used by us or any contract manufacturers to manufacture our product candidates must be approved by the FDA or other foreign regulatory authorities following inspections that will be conducted after we submit an application to the FDA or other foreign regulatory authorities.

If we engage contract manufacturers, we may not control the manufacturing process of, and may be completely dependent on, such contract manufacturing partners for compliance with cGMPs and any other regulatory requirements of the FDA or other regulatory authorities for the manufacture of our product candidates.

We have limited control over the ability of any contract manufacturers we engage to maintain adequate quality control, quality assurance and qualified personnel.

The facilities used by us or any third party contract manufacturers to manufacture our product candidates must be approved by the FDA or other foreign regulatory authorities following inspections that will be conducted after we submit an application to the FDA or other foreign regulatory authorities.

If we engage third party contract manufacturers, we may not control the manufacturing process of, and may be completely dependent on, such third party contract manufacturing partners for compliance with cGMPs and any other regulatory requirements of the FDA or other regulatory authorities for the manufacture of our product candidates.

We have limited control over the ability of any third party contract manufacturers we engage to maintain adequate quality control, quality assurance and qualified personnel.

Even with oversight, the third party may not be able to meet proper quality standard or its contractual obligations.

If the FDA or a comparable foreign regulatory authority does not approve these facilities for the manufacture of our product candidates or if it withdraws any approval in the future, we may need to find alternative manufacturing facilities, which would significantly impact our ability to develop, obtain regulatory approval for or market our product candidates, if licensed.

We, and any contract manufacturers we engage for registration-enabling clinical trials, may experience manufacturing difficulties due to limited manufacturing experience, resource constraints or as a result of labor disputes, the ongoing COVID-19 pandemic, the U.S.-China trade war or unstable political environments.

If we or any contract manufacturers we engage were to encounter any of these difficulties, our ability to manufacture sufficient product supply for our preclinical studies and clinical trials, or to provide products for patients once approved, would be jeopardized.

We, and any third party contract manufacturers we engage for registration-enabling clinical trials, may experience manufacturing difficulties due to limited manufacturing experience, resource constraints or as a result of labor disputes, the ongoing COVID-19 pandemic, the U.S.-China trade war or unstable political environments.

If we or any third party contract manufacturers we engage were to encounter any of these difficulties, our ability to manufacture sufficient product supply for our preclinical studies and clinical trials, or to provide products for patients once approved, would be jeopardized.

Many of the materials and regents we expect to use in our processes are single or sole source, and/or have limited stability and as such supply disruptions could materially impact our ability to develop or manufacture products.

4 unchanged sentences

There are no approved TCR-T immunotherapies for solid tumors.

While we plan to develop product candidates for use in solid tumors, including TSC-200, we cannot guarantee that our product candidates will show any functionality in the solid tumor microenvironment.

While we plan to develop product candidates for use in solid tumors, including the TSC-200 series, we cannot guarantee that our product candidates will show any functionality in the solid tumor microenvironment.

The cellular environment in which solid tumor cells thrive is generally hostile to T cells due to factors such as the presence of immunosuppressive cells, humoral factors and limited access to nutrients.

Our TCR-T-based product candidates may not be able to access the solid tumor, and even if they do, they may not be able to exert anti-tumor effects in a hostile tumor microenvironment.

Our TCR-T-based product candidates may not be able to access the solid tumor, and even if they do, they may not be able to exert anti-tumor effects in a hostile solid tumor microenvironment.

As a result, our product candidates may not demonstrate potency in solid tumors.

4 unchanged sentences

If we conduct any future clinical trials, we may not achieve a statistically significant result or the same level of statistical significance, if any, that we might have anticipated based on the results observed in our initial clinical trials.

In addition, patients who are undergoing allogeneic hematopoietic cell transplantation are very sick and may pass away from complications of their standard clinical transplantation thus making it difficult to ascertain the

beneficial effects of the added T-cell therapy.

In addition, patients who are undergoing allogeneic HCT are very sick and may pass away from complications of their standard clinical transplantation and treatments thus making it difficult to ascertain the beneficial effects of the added T cell therapy.

Further, toxicities of the T cell therapy would be difficult to distinguish from the toxicity of the transplantation itself.

Allogeneic HCT is a high-risk procedure that may result in complications or adverse events for patients in our clinical trials including those unrelated to the use of our products or for patients that use any of our product candidates, if approved.

Stem cell transplantation can cure patients across multiple diseases, but its use carries with it risks of toxicity, serious adverse events and death.

Because many of our therapies are used to prepare or treat patients undergoing allogeneic hematopoietic stem cell transplantation, patients in our clinical trials or patients that use any of our product candidates may be subject to many of the risks that are currently inherent to this procedure.

Because many of our therapies are used to prepare or treat patients undergoing allogeneic HCT, patients in our clinical trials or patients that use any of our product candidates may be subject to many of the risks that are currently inherent to this procedure.

In particular, stem cell transplant involves certain known potential post-procedure complications that may manifest several weeks or months after a transplant and which may be more common in certain patient populations.

2 unchanged sentences

All serious adverse events or unexpected side effects are continually monitored per the clinical trial’s approved protocol.

If serious adverse events are determined to be directly or specifically caused or exacerbated by our product candidates, we would follow the trial protocol’s requirements, which call for our data safety monitoring committee to review all available clinical data in making a recommendation regarding the trial’s continuation.

If serious adverse events are determined to be directly or specifically caused or exacerbated by our product candidates, we would follow the clinical trial protocol’s requirements, which call for our data safety monitoring committee to review all available clinical data in making a recommendation regarding the trial’s continuation.

We may not be able to file INDs or IND amendments to commence additional clinical trials on the timelines we expect, and even if we are able to, the FDA may not permit us to proceed.

We submitted INDs for TSC-100 and TSC-101 in the fourth quarter of 2021 and expect to submit IND applications for at least two of our four solid tumor TCR-T therapy candidates in the second half of 2022, with the remaining expected to be filed in 2023.

We are currently advancing multiple TCRs for six solid tumor targets:

HPV16 E7 (TSC-200), PRAME (TSC-203), MAGE-A1 (TSC-204), and the undisclosed targets of TSC-201, TSC-202 and TSC-205.

TSC-204-C0702 is an HLA-C*07:02-restricted TCR for

MAGE-A1 entering Phase 1 development;

TSC-204-A0201 is an HLA-A*02:01-restricted TCR for MAGE-A1 entering Phase 1 development;

TSC-200-A0201 is an HLA-A*02:01-restricted TCR for HPV16 E7 in IND-enabling activities;

and TSC-203-A0201 is an HLA-A*02:01-restricted TCR for PRAME in IND-enabling activities.

TCRs for the TSC-201 and TSC-202 programs are in lead optimization and discovery, respectively.

We expect to submit IND applications for additional TCRs in our solid tumor program throughout 2023.

However, we may not be able to file such INDs on the timelines we expect.

5 unchanged sentences

Our plan is to assess the safety and preliminary efficacy of multiplexed TCR-T therapy early in the clinical development of our product candidates (e.g., Phase 1).

We cannot guarantee, however, that the FDA will permit us to combine our product candidates with each other in a multiplexed TCR-T therapy before more extensive safety data are available for each individual product candidate or each variation or combination of a multiplexed TCR-T therapy.

While the FDA has cleared our T-Plex IND, which allows us to combine our product candidates with each other in a multiplexed TCR-T therapy, we must still provide safety data for each individual product candidate or each variation or combination of a multiplexed TCR-T therapy.

Any such requirements could result in material delays in the development timelines of our multiplexed TCR-T therapy candidates.

3 unchanged sentences

With a limited number of subjects and limited duration of exposure, rare and severe side effects of our product candidates may only be uncovered with a significantly larger number of patients exposed to the drug.

Because of the design of the dose escalation of our our planned Phase 1 clinical trials, undesirable side effects could also result in an expansion in the size of our clinical trials, increasing the expected costs and timeline of our clinical trials.

Because of the design of the dose escalation of our planned Phase 1 clinical trials, undesirable side effects could also result in an expansion in the size of our clinical trials, increasing the expected costs and timeline of our clinical trials.

Additionally, results of our clinical trials could reveal a high and unacceptable severity and prevalence of side effects or unexpected characteristics, which may stem from our therapies specifically or may be due to an illness from which the clinical trial subject is suffering.

For example, there could be an increased risk of graft-versus-host disease (GvHD) with the TCR-T treatment.

GvHD is a common toxicity in patients undergoing allogeneic hematopoietic stem cell transplantation, the focus of our liquid tumor program.

For example, there could be an increased risk of graft-versus-host disease (GvHD) with our TCR-T therapy in the post-HCT setting.

GvHD is a common toxicity in patients undergoing allogeneic HCT, the focus of our hematologic malignancies program.

GvHD occurs because donor T cells, which are part of the standard stem cell product, misrecognize antigens in the patient as foreign and attack tissues and organs that express those antigens.

26 unchanged sentences

Our product candidates may target healthy cells expressing target antigens leading to potentially fatal adverse effects.

Our product candidates target specific antigens that are also expressed on healthy cells.

Our product candidates target specific antigens that are also potentially expressed on healthy cells.

Our product candidates may target healthy cells, leading to serious and potentially fatal adverse effects.

4 unchanged sentences

If this peptide is expressed within normal tissues, our product candidates may target and kill the normal tissue in a patient, leading to serious and potentially fatal adverse effects.

Detection of any cross-reactivity may halt or delay any ongoing clinical trials for any TCR-T therapy candidate and prevent or delay regulatory approval.

Detection of any cross-reactivity may halt or delay any ongoing clinical trials for any of our TCR-T therapy candidate and prevent or delay regulatory approval.

Unknown cross-reactivity of the TCR-T binding domain to related proteins could also occur.

6 unchanged sentences

If the cancerous T cell is then administered to the patient with the TCR-T therapy candidates, the cancerous T cell could trigger the development of a new cancer in the patient.

We use non-viral transposon / transposase or lentiviral vectors to insert genetic information into T cells.

We use non-viral transposon / transposase to insert genetic information into T cells.

The risk of insertional oncogenesis remains a concern for gene therapy and we cannot assure that it will not occur in any of our ongoing or planned preclinical studies or clinical trials.

5 unchanged sentences

We may experience difficulties in patient enrollment in our clinical trials for a variety of reasons.

The timely completion of clinical trials in accordance with their protocols depends on, among other things, our ability to enroll a sufficient number of patients who remain in the clinical trial until its conclusion.

The timely completion of clinical trials in accordance with their approved protocols depends on, among other things, our ability to enroll a sufficient number of patients who remain in the clinical trial until its conclusion.

The enrollment of patients depends on many factors, including:

the patient eligibility criteria defined in the clinical trial protocol, particularly those who meet the requisite genetic criteria.

For example, for our liquid tumor program, patients would have to be HLA-A*02:01 positive and positive for the minor antigen HA-1 or HA-2 to be eligible for treatment with TSC-100 or TSC-101, respectively;

for our liquid tumor program, the ability to find a donor who has to be mismatched with the patient either for the HLA type or the minor antigen type to ensure that the engineered T-cell therapy does not recognize donor-derived blood cells;

For example, for our hematologic malignancies program, patients would have to be HLA-A*02:01 positive and positive for the minor antigen HA-1 or HA-2 to be eligible for treatment with TSC-100 or TSC-101, respectively;

for our hematologic malignancies program, the ability to find a donor who has to be mismatched with the patient either for the HLA type or the minor antigen type to ensure that the engineered T cell therapy does not recognize donor-derived blood cells;

the impact of the COVID-19 pandemic on clinical trial initiation and enrollment;

9 unchanged sentences

Since the number of qualified clinical investigators is limited, we expect to conduct some of our clinical trials at the same clinical trial sites that some of our competitors use, which will reduce the number of patients who are available for our clinical trials at such clinical trial sites.

Moreover, because our product candidates represent a departure from more commonly used methods for cancer treatment, potential patients and their doctors may be inclined to use conventional therapies, such as chemotherapy and hematopoietic stem cell transplantation, rather than enroll patients in any future clinical trial.

Moreover, because our product candidates represent a departure from more commonly used methods for cancer treatment, potential patients and their doctors may be inclined to use conventional therapies, such as chemotherapy and HCT, rather than enroll patients in any future clinical trial.

Additionally, because some of our clinical trials are expected to be in patients with relapsed/refractory cancer, the patients are typically in the late stages of their disease and may experience disease progression independent from our product candidates, making them unevaluable for purposes of the clinical trial and requiring additional patient enrollment.

23 unchanged sentences

If we are unable to identify suitable compounds for preclinical and clinical development, we will not be able to obtain revenues from sale of drugs in future periods, which likely would result in significant harm to our business prospects and financial position.

The market opportunities for our product candidates may be relatively small as it will be limited to those patients who are ineligible for or have failed prior treatments and our estimates of the prevalence of our target patient populations may be inaccurate.

The market opportunities for our product candidates may be relatively small as they will be limited to those patients who are ineligible for or have failed prior treatments and our estimates of the prevalence of our target patient populations may be inaccurate.

Cancer therapies are sometimes characterized as first line, second line, or third line, and the FDA often approves new therapies initially only for a particular line of use.

When cancer is detected early enough, first line therapy is sometimes adequate to cure the

cancer or prolong life without a cure.

When cancer is detected early enough, first line therapy is sometimes adequate to cure the cancer or prolong life without a cure.

Whenever first line therapy, usually chemotherapy, antibody drugs, tumor-targeted small molecules, hormone therapy, radiation therapy, surgery, or a combination of these, proves unsuccessful, second line therapy may be administered.

Second line therapies often consist of more chemotherapy, radiation, antibody drugs, tumor-targeted small molecules, or a combination of these.

Third line therapies can include hematopoietic stem cell transplantation in certain cancers, chemotherapy, antibody drugs and small molecule tumor-targeted therapies, more invasive forms of surgery and new technologies.

We expect to initially seek approval of our product candidates in most instances at least as a second or third line therapy, for use in patients to prevent relapse in patients undergoing hematopoietic stem cell transplantation.

Third line therapies can include HCT in certain cancers, chemotherapy, antibody drugs and small molecule tumor-targeted therapies, more invasive forms of surgery and new technologies.

We expect to initially seek approval of our product candidates in most instances at least as a second or third line therapy, for use in patients to prevent relapse in patients undergoing HCT.

Subsequently, for those product candidates that prove to be sufficiently safe and beneficial, if any, we would expect to seek approval as a second line therapy and potentially as a first line therapy, but there is no guarantee that our product candidates, even if licensed as a second or third or subsequent line of therapy, would be licensed for an earlier line of therapy, and, prior to any such approvals, we may have to conduct additional clinical trials.

61 unchanged sentences

Our competitors may be able to develop other products or drugs that are able to achieve similar or better results.

Our potential competitors include larger biotechnology and pharmaceutical companies with greater resources than us, academic institutions, governmental agencies, public and private research institutions and early stage or smaller companies.

Our potential competitors include larger biotechnology and pharmaceutical companies with greater resources than us, academic institutions, governmental agencies, public and private research

institutions and early stage or smaller companies.

Many of our competitors have substantially greater financial, technical and other resources, such as larger research and development staff, experienced marketing and manufacturing organizations and well-established sales forces.

Further, our competitors may have more financial resources, greater access to capital and diversified product offerings and revenue sources which may give our competitors an advantage over us in weathering the effects of the ongoing COVID-19 global pandemic.

In addition, many of these competitors are active in seeking patent protection and licensing arrangements in anticipation of collecting royalties for use of technology that they have developed.

3 unchanged sentences

We believe the key competitive factors that will affect the development and commercial success of our product candidates are safety, potency, purity, tolerability, reliability, convenience of use, price and reimbursement.

Specifically, by genetically engineering T-cell therapies, we face significant competition in the TCR space from multiple companies, including Kite Pharma Inc., a subsidiary of Gilead, Inc., Adaptimmune Therapeutics, Plc., Juno Therapeutics, Inc., a subsidiary of Bristol-Myers Squibb, Inc.

(including Yescarta, which is approved for the treatment for your large B-cell lymphoma or follicular lymphoma, two types of non-Hodgkin lymphoma), Iovance Biotherapeutics, Inc., Achilles Therapeutics plc, Geneos Therapeutics, Inc., PACT Pharma, Inc., Celyad, S.A., Fate Therapeutics, Inc., Nkarta, Inc., Medigene AG, Ziopharm Oncology, Inc., Bayer AG, Novartis AG (including Kymriah, which is approved for the treatment of B-cell acute lymphoblastic leukemia), Selecta Biosciences, Inc., TCR2 Therapeutics Inc., Adaptive Therapeutics, Inc., Immatics US, Inc., Lyell Immunopharma, Inc., Allogene Therapeutics, Inc., Sana Biotechnology, Inc., 3T Biosciences, Inc.

and Regeneron Pharmaceuticals, Inc.

Specifically, by genetically engineering T-cell therapies, we face significant competition in the TCR space from many companies.

For additional information regarding our competition, see “Item 1.

Business –

Competition”

in this Annual Report.

Even if we obtain regulatory approval of our product candidates, the availability and price of our competitors’

3 unchanged sentences

Our internal computer systems, or those used by our third party CROs or other contractors or consultants, may fail or suffer security breaches or other unauthorized or improper access, which could result in a material disruption of the development programs of our product candidates.

denial-of-service attacks, social engineering, and other events that affect service reliability and threaten the confidentiality, integrity, and availability of information), unauthorized access, natural disasters, fires, terrorism, war, telecommunications or electrical interruptions or failures, employee error or malfeasance or other malicious or inadvertent disruptions.

Despite the implementation of security measures, our internal computer systems and those of our current and future CROs and other contractors and consultants are vulnerable to a variety of disruptions and data privacy and information security incidents, including data breaches, attacks by hackers and other malicious third parties (including the deployment of computer viruses, malware, ransomware, denial-of-service attacks, social engineering, and other events that affect service reliability and threaten the confidentiality, integrity, and availability of information), unauthorized access, natural disasters, fires, terrorism, war, telecommunications or electrical interruptions or failures, employee error or malfeasance or other malicious or inadvertent disruptions.

For example, the ongoing conflict between Russia and Ukraine has led to an increase in cyberattacks on the Ukraine, including its government, companies, institutions and people, as well on the financial and communications infrastructure of other countries, companies and individuals therein.

Additionally, the increased usage of computers operated on home networks due to shelter-in-place, stay-at-home advisories or similar restrictions related to the COVID-19 pandemic may make our or our partners’

10 unchanged sentences

Our systems, servers and platforms and those of our service providers may be vulnerable to computer viruses or physical or electronic break-ins that our or their security measures may not detect.

Individuals able to circumvent such security measures may misappropriate our confidential or proprietary information, disrupt our operations, damage our computers or otherwise impair our reputation and business.

Individuals able to circumvent such security measures may misappropriate our confidential or proprietary

information, disrupt our operations, damage our computers or otherwise impair our reputation and business.

We may need to expend significant resources and make significant capital investments to protect against security breaches or to mitigate the impact of any such breaches.

11 unchanged sentences

Although we take reasonable measures to protect critical information and other data from unauthorized access, acquisition, use or disclosure, our information technology and infrastructure and that of our service providers handling and storing information on our behalf may be vulnerable to a variety of disruptions, including data breaches, attacks by hackers and other malicious third parties (including the deployment of computer viruses, malware, ransomware, denial-of-service attacks, social engineering, and other events that affect service reliability and threaten the confidentiality, integrity, and availability of information), unauthorized access, natural disasters, fires, terrorism, war, telecommunications or electrical interruptions or failures, employee error or malfeasance or other malicious or inadvertent disruptions.

In particular, the risk of a security breach or disruption, particularly through cyber-attacks or cyber intrusion, has generally increased as the number, intensity, and sophistication of attempted attacks and intrusions from around the world

have increased.

We may not be able to anticipate all types of security threats, and we may not be able to implement preventive measures that are effective against all such security threats.

11 unchanged sentences

The manufacture of our product candidates involves complex processes, including the manufacture of a transposon containing the genetic information for our TCR construct, a transposase used to insert the transposon genetic information into the T cell genome, and manufacturing operations to ensure the safety, integrity, strength, purity, and quality of the final product.

More specifically, the manufacture of our product candidates includes harvesting white blood cells from the patient, isolating certain T cells from the white blood cells, combining patient T cells with our delivery vector through a process known as transduction, selection of modified T cells from the population, expanding the selected transduced T cells to obtain the desired dose, aseptically filling product into vessels suitable for storage, distribution, and clinical dosing, and ultimately infusing the modified T cells back into the patient’s body.

dosing, and ultimately infusing the modified T cells back into the patient’s body.

As a result of the complexities entailed in this process, our manufacturing and supply costs will be higher than those at more traditional manufacturing processes and the manufacturing process is less reliable and more difficult to reproduce.

3 unchanged sentences

cells could result in delays in the manufacture and administration of our product candidates.

Although we plan to further expand our existing manufacturing facility, we currently rely on third parties for the manufacture of our vector and other components of our manufacturing process.

We currently rely on our internal manufacturing facility for clinical manufacturing, and any disruption to this facility could impact our ability to advance our clinical trials.

We currently rely on third parties for the manufacture of our vector and other components of our manufacturing process.

These third party manufacturers may incorporate their own proprietary processes into our components.

9 unchanged sentences

As our product candidates progress through preclinical studies and clinical trials towards licensure and commercialization, it is expected that various aspects of the manufacturing and administration process will be altered in an effort to optimize processes and results.

We have already identified some improvements to our manufacturing and administration processes, but these changes may not

achieve the intended objectives, and could cause our product candidates to perform inadequately affecting the results of ongoing or future clinical trials.

We have already identified some improvements to our manufacturing and administration processes, but these changes may not achieve the intended objectives, and could cause our product candidates to perform inadequately affecting the results of ongoing or future clinical trials.

In addition, such changes may require amendments to be made to regulatory applications or necessitate development of new or additional TCR constructs and further clinical testing, which may further delay the timeframes under which modified manufacturing processes can be used for any of our product candidates.

4 unchanged sentences

We may ultimately be unable to reduce the expenses associated with our product candidates to levels that will allow us to achieve a profitable return on investment.

We plan to further expand our existing manufacturing facility and infrastructure in lieu of relying on third parties for the manufacture of our product candidates for certain clinical purposes and the use of third party manufacturing suites, which will be costly, time-consuming, and which may not be successful.

We are in the process of expanding our existing manufacturing capacity to support our Phase 1 and Phase 2 clinical trials for TSC-100, TSC-101, TSC-102, TSC-200, TSC-201, TSC-202, and TSC-203.

We have no experience as a company in setting up, building or managing a manufacturing facility or manufacturing suite, and may never be successful in developing our own manufacturing suite, manufacturing facility or manufacturing capability.

Although we have expanded our existing manufacturing facility and infrastructure in lieu of relying solely on third parties for the manufacture of our product candidates for certain clinical purposes and many of our personnel have experience in clinical manufacturing at other companies, we have no direct experience as a company managing manufacturing for our product candidates, which will be costly, time-consuming, and which may not be successful.

We have expanded our existing manufacturing capacity to support our Phase 1 and Phase 2 clinical trials of our product candidates.

We have no prior experience as a company in setting up, building or managing a manufacturing facility or manufacturing suite, and may never be successful in developing our own manufacturing suite, manufacturing facility or manufacturing capability.

We will need to hire additional personnel to manage our operations and facilities and develop the necessary infrastructure to continue the research and development, and eventual commercialization, if licensed, of our product candidates.

If we fail to recruit the required personnel, manage our growth effectively, have inadequate facility design or construction, or fail to select the correct location, the development and production of our product candidates could be curtailed or delayed.

Even if we are successful in establishing a manufacturing suite or manufacturing facility, our manufacturing capabilities could be affected by cost-overruns, unexpected delays, equipment failures, design or construction flaws, labor shortages, supply disruptions, natural disasters, power failures and numerous other factors that could prevent us from realizing the intended benefits of our manufacturing strategy and have a material adverse effect on our business.

Although we have established a manufacturing facility, our manufacturing capabilities could be affected by cost-overruns, unexpected delays, equipment failures, design or construction flaws, labor shortages, supply disruptions, natural disasters, power failures and numerous other factors that could prevent us from realizing the intended benefits of our manufacturing strategy and have a material adverse effect on our business.

In addition, the FDA, the European Medicines Agency (EMA), and other foreign regulatory authorities may require us to submit samples of any lot of any licensed product together with the protocols showing the results of applicable tests at any time.

6 unchanged sentences

We may have difficulty validating our manufacturing process as we manufacture TCR-T therapy candidates from an increasingly diverse patient population for our clinical trials.

We have limited process development experience and have not yet established lot to lot or donor consistency with healthy or unhealthy donors.

As we develop our clinical products, we may encounter unforeseen difficulties due to quality, quantity, supply timing, or variability issues with donor starting materials and may not be able to develop a robust process or incur additional costs or delays in developing a robust process due to starting material variation or supply.

22 unchanged sentences

Securing regulatory approval also requires the submission of information about the biologic manufacturing process and inspection of manufacturing facilities by the relevant regulatory authority.

The FDA or comparable foreign regulatory authorities may fail to approve our manufacturing processes or facilities, whether run by us or our contract manufacturing organizations (CMOs).

The FDA or comparable foreign regulatory authorities may fail to approve our manufacturing processes or facilities, whether run by us or our third-party CMOs.

In addition, if we make manufacturing changes to our product candidates in the future, we may need to conduct additional preclinical or clinical studies to bridge our modified product candidates to earlier versions.

21 unchanged sentences

Any delay in obtaining, or inability to obtain, applicable regulatory approval would delay or prevent commercialization of our product candidates and would materially adversely impact our business and prospects.

We may seek orphan drug status for TSC-100, TSC-101, TSC-102, TSC-200, TSC-201, TSC-202, and TSC-203 and some of our other future product candidates, but we may be unable to obtain such designations or to maintain the benefits associated with orphan drug status, including market exclusivity, which may cause our revenue, if any, to be reduced.

We may seek orphan drug status for some of our current or future product candidates, but we may be unable to obtain such designations or to maintain the benefits associated with orphan drug status, including market exclusivity, which may cause our revenue, if any, to be reduced.

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 in the United States, or a patient population greater than 200,000 in the United States when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the United States will be recovered from sales in the United States for that drug or biologic.

1 unchanged sentence

In the United States, orphan drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers.

After the FDA grants orphan drug

designation, the generic identity of the drug and its potential orphan use are disclosed publicly by the FDA.

After the FDA grants orphan drug designation, the generic identity of the drug and its potential orphan use are disclosed publicly by the FDA.

Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

2 unchanged sentences

Furthermore, the FDA can waive orphan exclusivity if we are unable to manufacture sufficient supply of our product.

We may seek orphan drug designation for TSC-100, TSC-101, TSC-102, TSC-200, TSC-201, TSC-202, and TSC-203 and some or all of our other future product candidates in additional orphan indications in which there is a medically plausible basis for the use of these products.

We may seek orphan drug designation for some or all of our current or future product candidates in additional orphan indications in which there is a medically plausible basis for the use of these products.

Even when we obtain orphan drug designation, exclusive marketing rights in the United States may be limited if we seek licensure for an indication broader than the orphan designated indication and may be lost if the FDA later determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

3 unchanged sentences

The new legislation reverses prior precedent holding that the Orphan Drug Act unambiguously requires that the FDA recognize the orphan exclusivity period regardless of a showing of clinical superiority.

Moreover, in the Consolidated Appropriations Act of 2021, Congress did not further change this interpretation when it clarified that the interpretation codified in FDARA would apply in cases where FDA issued an orphan designation before the enactment of FDARA but where product approval came after the enactment of FDARA.

The FDA may further reevaluate the Orphan Drug Act and its regulations and policies.

2 unchanged sentences

A Breakthrough Therapy designation by the FDA, even if granted for any of our product candidates, may not lead to a faster development or regulatory review or approval process and it does not increase the likelihood that our product candidates will receive marketing approval.

We plan to seek a Breakthrough Therapy designation for TSC-100, TSC-101, TSC-102, TSC-200, TSC-201 and TSC-202 and may seek Breakthrough Therapy designation for some or all of our future product candidates.

We plan to seek a Breakthrough Therapy designation for our current product candidates and may seek Breakthrough Therapy designation for some or all of our future product candidates.

A breakthrough therapy is defined as a drug or biologic that is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug, or biologic, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

6 unchanged sentences

Thus, even though we intend to seek Breakthrough Therapy designation for TSC-100 and some or all of our future product candidates for the treatment of various cancers, there can be no assurance that we will receive breakthrough therapy designation.

A Fast Track designation by the FDA, even if granted for TSC-102, TSC-200, TSC-201, TSC-202, and TSC-203 or any other future product candidates, may not lead to a faster development or regulatory review or approval process, and does not increase the likelihood that our product candidates will receive marketing approval.

A Fast Track designation by the FDA, even if granted for any of our current or future product candidates, may not lead to a faster development or regulatory review or approval process, and does not increase the likelihood that our product candidates will receive marketing approval.

If a drug is intended for the treatment of a serious or life-threatening condition and the drug demonstrates the potential to address unmet medical needs for this condition, the drug sponsor may apply for FDA Fast Track designation for a particular indication.

We plan to seek Fast Track designation for TSC-100, TSC-101, TSC- 200, TSC-201, TSC 202, and TSC-203 and may seek Fast Track designation

for certain of our future product candidates, but there is no assurance that the FDA will grant this status to any of our proposed product candidates.

We plan to seek Fast Track designation for our current product candidates and may seek Fast Track designation for certain of our future product candidates, but there is no assurance that the FDA will grant this status to any of our proposed product candidates.

Marketing applications filed by sponsors of products in Fast Track development may qualify for priority review under the policies and procedures offered by the FDA, but the Fast Track designation does not assure any such qualification or ultimate marketing approval by the FDA.

3 unchanged sentences

In addition, the FDA may withdraw any Fast Track designation at any time.

Accelerated approval by the FDA, even if granted for TSC-100, TSC-101, TSC-102, TSC-200, TSC-201, TSC-202, and TSC-203 or any other future product candidates, may not lead to a faster development or regulatory review or approval process and it does not increase the likelihood that our product candidates will receive marketing approval.

We plan to seek approval of TSC-100, TSC-101, TSC-102, TSC-200, TSC-201, TSC-202, and TSC-203, and may seek approval of future product candidates using FDA’s accelerated approval pathway.

We may seek accelerated approval from the FDA for any of our current or future product candidates.

Accelerated approval, even if granted, for any of our current or future product candidates, may not lead to a faster development, or regulatory review or approval process and it does not increase the likelihood that our product candidates will receive marketing approval.

We plan to seek approval of our current product candidates, and may seek approval of future product candidates using FDA’s accelerated approval pathway.

A product may be eligible for accelerated approval if it treats a serious or life-threatening condition and generally provides a meaningful advantage over available therapies.

In addition, it must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit.

As a condition of approval, the FDA may require that a sponsor of a drug or biologic receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

As a condition of approval, the FDA may require that a sponsor of a drug or biologic receiving accelerated approval perform adequate and well-controlled post-marketing clinical

These confirmatory trials must be completed with due diligence.

In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

Even if we do receive accelerated approval, we may not experience a faster development or regulatory review or approval process, and receiving accelerated approval does not provide assurance of ultimate FDA approval.

In addition, the FDA currently requires, unless otherwise informed by the agency, pre-approval of promotional materials for products receiving accelerated approval, which could adversely impact the timing of the commercial launch of the product.

Even if we do receive accelerated approval, we may not experience a faster development, regulatory review or approval process for that product.

In addition, receiving accelerated approval does not provide assurance of ultimate FDA approval.

We may seek designation for our TargetScan platform as a designated platform technology, but we might not receive such designation, and even if we do, such designation may not lead to a faster regulatory review or approval process .

We may seek designation for our TargetScan platform as a designated platform technology.

Under FDORA, a platform technology incorporated within or utilized by a biological product is eligible for designation as a designated platform technology if (1) the platform technology is incorporated in, or utilized by, a biological product approved under an BLA;

If so designated, the FDA may expedite the development and review of any subsequent original BLA for a biological product that uses or incorporates the platform technology.

Even if we believe our TargetScan platform technology meets the criteria for such designation, the FDA may disagree and instead determine not to grant such designation.

In addition, the receipt of such designation for a platform technology does not ensure that a biological product will be developed more quickly or receive FDA approval.

Moreover, the FDA may revoke a designation if the FDA determines that a designated platform technology no longer meets the criteria for such designation.

8 unchanged sentences

If we fail to comply with the regulatory requirements in international markets and/or receive applicable marketing approvals, our target market will be reduced and our ability to realize the full market potential of our product candidates will be harmed.

In addition, the United Kingdom left the European Union on January 31, 2020, an event commonly referred to as “Brexit,”

and following the “transition period,”

on December 30, 2020, the European Union, the European Atomic Energy Community and the United Kingdom signed a Trade and Cooperation Agreement.

Brexit imposes new regulatory costs and challenges that may have a material adverse effect on us and our operations.

We may face decreased chances to obtain market approval for our product candidates in the European Union, including the possibility that the European Medicines Agency will not accept data from our clinical trials conducted in the United Kingdom or will only do so if we comply with certain conditions.

Conversely, since a significant proportion of the United Kingdom’s regulatory framework affecting the pharmaceutical and biotechnological industry is derived from European Union directives and regulations, Brexit could materially alter the regulatory regime with respect to our product candidates in the United Kingdom, which may increase the time and costs associated with obtaining regulatory approval from the relevant authorities.

It may also be time-consuming and expensive for us to alter our internal operations in order to comply with new regulations.

Altered regulations could also add time and expense to the process by which our product candidates receive regulatory approval in the United Kingdom and the European Union.

In addition, we could face heightened risks with respect to seeking marketing approval in the United Kingdom as a result of the withdrawal of the United Kingdom from the European Union, commonly referred to as Brexit.

The United Kingdom is no longer part of the European Single Market and European Union Customs Union.

As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or the MHRA, became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law, whereas Northern Ireland will continue to be subject to European Union rules under the Northern Ireland Protocol.

The MHRA will rely on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended), or the HMR, as the basis for regulating medicines.

The HMR has incorporated into the domestic law of the body of European Union law instruments governing medicinal products that pre-existed prior to the United Kingdom’s withdrawal from the European Union.

Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, may force us to restrict or delay efforts to seek regulatory approval in the United Kingdom for our product candidates, which could significantly and materially harm our business.

Furthermore, following the Brexit vote, the European Union moved the European Medicines Agency’s headquarters from the United Kingdom to the Netherlands.

This transition may cause disruption in the administrative and medical scientific links between the European Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency, including delays in granting clinical trial authorization or marketing authorization, disruption of import and export of active substance and other components of new drug formulations and disruption of the supply chain for clinical trial product and final authorized formulations.

formulations and disruption of the supply chain for clinical trial product and final authorized formulations.

The cumulative effects of the disruption to the regulatory framework may add considerably to the development lead time to marketing authorization and commercialization of products in the European Union and/or the United Kingdom.

4 unchanged sentences

These requirements include submissions of safety and other post-marketing information and reports, registration, as well as continued compliance with cGMPs, cGTPs and good clinical practices (GCPs) for any clinical trials that we conduct post-licensure.

Manufacturers and manufacturers’

facilities are required to comply with extensive FDA, and comparable foreign regulatory authority requirements, including ensuring that quality control and manufacturing procedures conform to cGMP regulations and applicable product tracking and tracing requirements.

Later discovery of previously unknown problems with our product candidates, including adverse events of unanticipated severity or frequency, or with our manufacturing processes (or those of third parties we engage), or failure to comply with regulatory requirements, may result in, among other things:

restrictions on the marketing or manufacturing of our product candidates, withdrawal of the product from the market or voluntary or mandatory product recalls;

under FDORA, sponsors of approved drugs and biologics must provide 6 months’

notice to the FDA of any changes in marketing status, such as the withdrawal of a product, and failure to do so could result in the FDA placing the product on a list of discontinued products, which would revoke the product’s ability to be marketed;

revisions to the labeling, including limitation on approved uses or the addition of additional warnings, contraindications or other safety information, including boxed warnings;

24 unchanged sentences

Government authorities and other third party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels.

The availability of coverage and extent of reimbursement by governmental and private payors is essential for most patients to be able to afford treatments such as gene therapy products.

The availability of coverage and extent of reimbursement by governmental and private payors is essential for most patients to be able to afford treatments such as cell therapy products.

Sales of these or other product candidates that we may identify will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by health maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health administration authorities, private health coverage insurers and other third party payors.

16 unchanged sentences

There is also significant uncertainty related to the insurance coverage and reimbursement of newly approved products and coverage may be more limited than the purposes for which the medicine is approved by the FDA or comparable foreign regulatory authorities.

In the United States, the principal decisions about reimbursement for new medicines are typically made by CMS, an agency within HHS.

In the United States, the principal decisions about reimbursement for new medicines are typically made by Centers for Medicare & Medicaid Services, or CMS, an agency within the HHS.

CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare and private payors tend to follow CMS to a substantial degree.

8 unchanged sentences

Our inability to promptly obtain coverage and profitable payment rates from both government-funded and private payors for any approved products we may develop could have a material adverse effect on our operating results, our ability to raise capital needed to commercialize product candidates, and our overall financial condition.

Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices

than in the United States.

Our inability to promptly obtain coverage and profitable reimbursement rates third party payors for any approved products that we develop could have a material adverse effect on our operating results, our ability to raise capital needed to commercialize products and our overall financial condition.

Increasingly, t

Our inability to promptly obtain coverage and profitable reim

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business