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Item 1. Business

2025-03-05 compared with 2024-03-06 · 388 added, 537 removed, 822 unchanged (53% of the section changed)

We are a clinical-stage biopharmaceutical company focused on developing a robust pipeline of T cell receptor (TCR)-engineered T cell, or TCR-T, therapies for the treatment of patients with cancer.

We are a clinical-stage biotechnology company focused on developing a robust pipeline of T cell receptor (TCR)-engineered T cell, or TCR-T, therapies for the treatment of patients with cancer.

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

Over the past several years, we have built our ImmunoBank, a repository of therapeutic TCRs that recognize diverse targets and are associated with multiple human leukocyte antigen, or HLA, types.

These TCRs are then used to manufacture enhanced TCR-T therapies to treat a broad population of patients with both heme and solid tumor malignancies.

We then use these TCRs to manufacture enhanced TCR-T therapies to treat a broad population of patients with both hematologic, or heme, and solid tumor malignancies.

Every TCR in our ImmunoBank has come from our proprietary platform technologies, and we are continuing to expand our ImmunoBank.

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 then use these anti-cancer TCRs to treat patients by genetically engineering T cells to recognize and eliminate their cancer.

In addition to discovering TCRs against novel targets, we are using our ReceptorScan technology to identify high affinity naturally occurring TCRs for known targets.

Once we identify therapeutic candidates using these technologies, we reduce the safety risk of clinical development by comprehensively screening these TCRs against the human proteome using SafetyScan to identify potential off-target interactions.

We then eliminate any TCR-T candidates that cross-react with proteins expressed at high levels in normal tissues.

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

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

This system is highly reproducible and can be routinely applied to new TCR-T candidates in a cost-effective manner without the need for extensive process development.

The larger cargo capacity of our non-viral vector delivery system allows us to include additional T cell enhancements in our product candidates.

In both our heme and solid tumor programs, we are introducing the gene for CD8α/β along with the TCR gene, which enables us to engineer both cytotoxic and helper T cells.

We believe this enhancement has the potential to improve responses to TCR-T therapy in the clinic compared to engineering cytotoxic T cells alone.

In our solid tumor program, we are also adding a dominant-negative (DN) form of TGFβRII to our T cells, which enables them to proliferate despite the presence of TGFβ in the hostile tumor microenvironment.

This has the potential to enhance T cell persistence.

Our GMP facility has the estimated capacity to manufacture clinical trial materials for up to 250 TCR-T components per year, sufficient to support all of our programs through Phase 2 clinical development.

We are advancing a robust pipeline of TCR-T 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 disease and prevent relapse following allogeneic hematopoietic cell transplantation (HCT).

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

Our lead product candidates, TSC-100 and TSC-101, are in development for the treatment of patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL), who are undergoing allogeneic hematopoietic cell transplantation (HCT).

The products are designed to eliminate residual disease and promote complete donor chimerism, thereby preventing relapse.

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

We have initiated a multi-arm Phase 1 "umbrella" clinical study of TSC-100 and TSC-101 with over ten clinical sites activated, and we plan to add more sites in 2024.

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

We are currently conducting a multi-arm Phase 1 "umbrella" clinical study of TSC-100 and TSC-101, the ALLOHA Phase 1 heme trial, with 15 clinical sites activated, and we plan to open additional sites before the end of 2025.

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

One of the challenges of treating solid tumors is that they are heterogeneous – not every tumor cell expresses a given target and some tumor cells lose half their HLA genes.

To address this challenge, we are developing what we refer to as multiplexed TCR-T therapy - treating a patient with more than one TCR-T candidate at a time.

We are designing these multiplexed therapies to be a simultaneous administration of up to three highly active TCR-T therapy candidates, selected from our ImmunoBank, that are customized for each patient based on which targets are expressed in their tumors and which HLA genes are still intact.

We continue to prioritize expanding the ImmunoBank with TCRs for multiple targets and multiple HLA types for each target.

We have now advanced six TCR-T therapy candidates into Phase 1 development for solid tumors:

To address this challenge, we are developing what we refer to as multiplex TCR-T therapy, or T-Plex, in which we treat a patient with more than one TCR-T therapy product candidate at a time.

We are designing these multiplex therapies to be a simultaneous administration of up to three highly active TCR-T therapy product candidates, selected from our ImmunoBank, that are customized for each patient based on which targets are expressed in their tumors and which HLA genes are still intact.

We continue to prioritize expanding the ImmunoBank with TCRs for additional targets and multiple HLA types for each target.

We have now advanced seven TCR-T therapy product candidates into Phase 1 development for solid tumors:

TSC-203-A0201 (PRAME, HLA-A*02:01);

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TSC-202-A0201 (MAGE-A4, HLA-A*02:01);

TSC-204-A0201 (MAGE-A1, HLA-A*02:01);

TSC-204-C0702 (MAGE-A1, HLA-C*07:02);

and TSC-204-A0101 (MAGE-A1, HLA-A*01:01).

In addition to clearing these six solid-tumor investigational new drug (IND) applications, the FDA has cleared our IND application for T-Plex, enabling us to treat patients with multiplexed TCR-T therapy.

We plan to further expand the ImmunoBank in 2024 by filing IND applications for additional TCR-Ts.

In addition to clearing these seven solid-tumor investigational new drug (IND) applications, the U.S.

Food and Drug Administration (FDA) has cleared our IND application for T-Plex, enabling us to treat patients with multiplex TCR-T therapy.

We plan to further expand the ImmunoBank by filing IND applications for additional TCR-T therapy product candidates.

We have initiated a Phase 1 solid tumor clinical trial, the PLEXI-T trial, with 15 clinical sites activated, and we plan to open additional sites before the end of 2025.

We have an internal good manufacturing practices, or GMP, facility to manufacture clinical supply for our TCR-T therapy product candidates.

This facility allows us to rapidly, cost-effectively, and consistently manufacture our TCR-Ts.

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

This non-viral platform approach can be rapidly applied to new TCR-T therapy product candidates in a cost-effective manner without the need for extensive process development.

The larger cargo capacity of our non-viral vector delivery system allows us to include additional T cell enhancements in our product candidates.

In both our heme and solid tumor programs, we are introducing the gene for CD8α/β along with the TCR gene, which enables us to engineer both cytotoxic and helper T cells with our TCRs.

We believe this enhancement has the potential to improve responses to TCR-T therapy in the clinic compared to engineering cytotoxic T cells alone.

This has the potential to enhance T cell persistence.

Our GMP facility has the estimated capacity to manufacture clinical trial materials for up to 250 TCR-T components per year.

To further increase our existing clinical manufacturing capacity and prepare for potential commercialization, we have engaged a global contract development and manufacturing organization, or CDMO, with worldwide commercial capabilities to support both the heme and solid tumor programs.

The CDMO is on track to add capacity and to support additional clinical manufacturing of the heme program in the second half of 2025.

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

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If their T-cells 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 hematologic malignancies.

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

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

In contrast, CAR-T therapy has proven effective

in certain heme malignancies of lymphoid origin but has shown only limited activity in myeloid malignancies or solid tumors.

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.

The successful development of TCR-Ts has three key prerequisites:

The successful development of TCR-T therapy product candidates has three key prerequisites:

(i) an effective anti-cancer TCR;

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We believe our approach provides us with the following key advantages:

• Our TCR-Ts are based on highly active TCRs that are clinically relevant.

• Our TCR-T therapy product candidates are based on highly active TCRs that are clinically relevant.

Many other approaches to T cell therapy rely on specifically expanding T cells that are already present in the patient.

Our platform analyzes anti-cancer T cells from a broad set of individuals, including patients responding to immunotherapy as well as healthy donors, to find the most active and clinically relevant TCRs against each target.

We believe that we can develop TCR-Ts for a wide range of patients, including those who do not have T cells that efficiently recognize their cancers.

• Our TCR-Ts are designed to be used in combination with each other.

We have built the ImmunoBank of TCRs to allow for multiplexed TCR-T, which has the potential to address the heterogeneous nature of solid tumors and prevent resistance developing due to target or HLA loss.

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

We believe that we can develop TCR-T therapy product candidates for a wide range of patients, including those who do not have T cells that efficiently recognize their cancers.

• Our TCR-T therapy product candidates are designed to be used in combination with each other.

We have built the ImmunoBank of TCRs to allow for multiplexed TCR-T therapy, which has the potential to address the heterogeneous nature of solid tumors and address resistance due to target or HLA loss.

We continue to expand the ImmunoBank with TCRs for additional targets as well as multiple common HLA types for each target.

• Our approach is expandable.

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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:

(i) discover anti-cancer TCRs from patients with exceptional responses to immunotherapy;

(ii) determine novel targets of clinically relevant TCRs;

(iii) discover novel TCRs that recognize clinically validated targets;

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

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

The central elements of our platform that we believe 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.

We have developed this technology to be extremely versatile and applicable across multiple therapeutic areas, including cancer, autoimmune disorders, and infectious diseases.

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

Using TargetScan, we have identified approximately 200 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 we have also already identified

highly active TCRs that recognize these targets.

Two of our pipeline programs emerged from TargetScan:

TSC-201-B0702 (MAGE-C2, HLA-B*07:02) and TSC-204-C0702 (MAGE-A1, HLA-C*07:02), the latter of which was featured in the peer-reviewed journal Cell in 2022.

ReceptorScan.

To further expand our ability to discover and develop therapeutic TCRs, we have developed our proprietary ReceptorScan technology to enable us to identify and clone highly active TCRs that recognize known or clinically validated targets.

We co-culture hundreds of millions of CD8+ T cells from either healthy donors or cancer patients with dendritic cells, also referred to as antigen-presenting cells, that display the target antigen of interest to the T cells.

T cells that recognize the target of interest proliferate and are subsequently isolated based on their ability to recognize a fluorescently labeled version of the target.

We then use single cell sequencing to identify the specific TCR sequences that recognize the target.

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 candidates, TSC-100 targeting HA-1 and TSC-101 targeting HA-2, as well as several other pipeline programs, including TSC-203-A0201 (PRAME, HLA-A*02:01) and TSC-200-A0201 (HPV16, HLA-A*02:01).

SafetyScan is designed to identify potential off-target interactions of a given TCR and eliminate those TCR candidates that cross-react with proteins expressed at high levels in normal tissue.

We believe this will allow us to reduce the risk and enhance the potential safety profile of our TCR-T candidates early in development before we initiate clinical trials.

We are expanding the ImmunoBank, our diverse repository 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 HLA haplotype.

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

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

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

We have built the ImmunoBank to be compatible with autologous, allogeneic, and in vivo engineering technologies in order to potentially transition to generating off-the-shelf products for direct, customized administration to patients.

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

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

Our TCR-T candidates are manufactured using a transposon/transposase system, in which the DNA encoding the TCR is manufactured as a Nanoplasmid , a non-viral vector.

The Nanoplasmid, together with an mRNA sequence encoding a transposase enzyme, is introduced into the T cell by electroporation.

After the T cell translates the mRNA into protein, the transposase enzyme inserts the TCR sequence from the Nanoplasmid, as well as any enhancements such as CD8 a / b and DN-TGF b RII, into the genome of the T cell.

This system is highly reproducible, as the only required components are a Nanoplasmid, which is different for each TCR product, and an mRNA, which is constant for all TCR products.

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

We have completed the construction and qualification 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-Ts.

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.

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

We have successfully manufactured TSC-100 and TSC-101 and have dosed patients in our hematological malignancies program.

The FDA has additionally cleared seven IND applications for our solid tumor program, including our primary IND application T-Plex, which supports the use of multiple TCR-Ts to create customized multiplexed TCR-T therapy, as well as IND applications for TSC-200-A0201 (HPV16, HLA-A*02:01), TSC-201-B0702 (MAGE-C2, HLA-B*07:02), TSC-203-A0201 (PRAME, HLA-A*02:01), TSC-204-A0201 (MAGE-A1, HLA-A*02:01), TSC-204-C0702 (MAGE-A1, HLA-C*07:02), and TSC-204-A0101 (MAGE-A1, HLA-A*01:01), in our view further validating our manufacturing capabilities.

We are expanding the ImmunoBank with the goal of delivering customized multiplexed TCR-T therapy 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.

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

Our lead product candidates, TSC-100 and TSC-101, are in development for the treatment of patients with heme malignancies to eliminate residual disease and prevent relapse following HCT.

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

We have developed and continue to expand the ImmunoBank with the goal of delivering customized multiplex TCR-T therapy to a wide range of patients with cancer.

Our current proprietary pipeline is summarized in the figure below.

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Amgen will evaluate a variety of modalities to create therapeutic candidates based on targets discovered by TScan and will retain all global development and commercial rights.

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

Our Hematologic Malignancies Program.

We are developing TCR-T therapies to treat patients with heme malignancies, including acute myeloid leukemia, or AML, myelodysplastic syndromes, or MDS, and acute lymphocytic leukemia, or ALL, who are undergoing allogeneic HCT.

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

Our Heme Program.

We are developing TCR-T therapy product candidates to treat patients with heme malignancies, including AML, MDS, and 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.

We are currently enrolling patients in a multi-arm Phase 1 "umbrella" clinical study with over ten clinical sites activated and additional sites planned to be added in 2024.

Additionally, we are planning to expand our heme program to include additional HLA types.

We have now advanced TSC-102-A0301, which targets an HLA-A*03:01-restricted epitope on CD45, into IND-enabling activities.

We are currently enrolling patients in a multi-arm Phase 1 "umbrella" clinical study with 15 clinical sites activated and additional sites planned to be opened in 2025.

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.

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

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 candidates for solid tumors.

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

Our Solid Tumor Program .

We are developing a portfolio of autologous TCR-T candidates designed to be used in combination with each other to treat and eliminate solid tumors.

Our TSC-20X 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 candidates include:

(i) 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

Our first six product candidates include a combination of known targets, such as HPV16 for TSC-200, the previously undisclosed target of MAGE-A4 for TSC-202, PRAME for TSC-203, and MAGE-A1 for TSC-204, as well as a target that is a novel antigen for TCR-T therapy, MAGE-C2 for TSC-201.

In addition to our six lead product candidates, we have identified approximately 200 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 the ImmunoBank to enable customized multiplexed TCR-T therapy for a wide range of solid tumor patients.

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

We are developing a portfolio of autologous TCR-T therapy product candidates designed to be used in combination with each other to treat and eliminate solid tumors.

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

Our TCR-T therapy product candidates include:

(i) well-recognized cancer targets that have demonstrated anti-tumor activity in clinical trials as well as 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 seven product candidates address known and novel targets:

E7 of HPV16 for TSC-200-A0201, MAGE-C2 for TSC-201-B0702, MAGE-A4 for TSC-202-A0201, PRAME for TSC-203-A0201, and MAGE-A1 for TSC-204-A0201, TSC-204-C0702, and TSC-204-A0101.

We have built and continue to expand the ImmunoBank to enable customized multiplex TCR-T therapy for a wide range of solid tumor patients.

Our initial solid tumor indications include non-small cell lung cancer, sarcoma, head & neck cancer, cervical cancer, and anal & genital cancer.

For each patient with a solid tumor malignancy, we first analyze the patient's tumor to determine which targets are expressed at high levels and which HLA genes are still intact.

We 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 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 multiplex TCR-T therapy.

Enabled by the additional cargo capacity of our non-viral vector delivery system, we are also introducing enhancements to our product candidates to deepen tumor responses and prolong duration of response.

By introducing the gene for CD8α/β along with the TCR gene, we are able to engineer both cytotoxic and helper T cells, which we believe has the potential to improve responses to treatment with TCR-T therapy in the clinic compared to engineering cytotoxic T cells alone.

We are also adding a DN-TGFβRII to T cells, which allows them to proliferate despite the presence of TGFβ in the hostile tumor microenvironment.

We are also adding DN-TGFβRII to T cells, which allows them to proliferate despite the presence of TGFβ in the hostile tumor microenvironment.

This has the potential to enhance T cell persistence.

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We intend to opportunistically pursue collaborations with strategic partners for applications of our platform technologies outside our core focus of oncology.

Our mission is to create life-changing TCR-T 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 hematologic malignancies and solid tumors.

Our mission is to create life-changing TCR-T therapy product candidates for patients by unleashing the untapped potential of the human immune system.

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

Our strategy includes the following key elements:

• 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.

To ensure that the antigens identified are clinically relevant, we use TCRs from tumor samples of patients with exceptional responses to immunotherapy.

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

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

We continue to prioritize expanding 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 and HLA loss.

• 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.

Using our ReceptorScan technology, we generated hundreds of highly active TCRs that recognize HA-1 and HA-2.

We selected TSC-100 and TSC-101 based on their superior potency and lack of off-target effects.

We are currently enrolling patients in a multi-arm Phase 1 clinical study of TSC-100 and TSC-101 with over ten clinical sites activated, with additional sites planned to be added in 2024.

We are currently enrolling patients in a multi-arm Phase 1 clinical study of TSC-100 and TSC-101 with 15 clinical sites activated and additional sites planned to be added in 2025.

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 hematologic malignancies program, we have established a foundation of manufacturing, clinical and regulatory capabilities to support the development of our broad portfolio of TCR-Ts.

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

We are initially developing our TSC-20X series of TCR-Ts against five selected target antigens that are frequently expressed across multiple solid tumor types.

Our first six solid tumor TCR-T candidates include a combination of known targets, such as HPV16 for TSC-200, MAGE-A4 for TSC-202, PRAME for

TSC-203, and MAGE-A1 for TSC-204, as well as a target that is a novel antigen for TCR-T therapy, MAGE-C2 for TSC-201.

We believe that the treatment of solid tumors will require a combination of several therapeutic TCRs, which we refer to as 'multiplexed therapy'.

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

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

In addition, through our heme malignancies program, we have established a foundation of manufacturing, clinical and regulatory capabilities to support the development of our broad portfolio of TCR-T therapy product candidates.

• Advance our solid tumor program through clinical development.

We are initially developing our solid tumor TCR-T therapy product candidates against five selected target antigens that are frequently expressed across multiple solid tumor types.

Our first seven solid tumor TCR-T therapy product candidates address known and novel targets, including E7 of HPV16 for TSC-200-A0201, MAGE-C2 for TSC-201-B0702, MAGE-A4 for TSC-202-A0201, PRAME for TSC-203-A0201, and MAGE-A1 for TSC-204-A0201, TSC-204-C0702, and TSC-204-A0101.

We believe that the treatment of solid tumors will require a combination of several therapeutic TCRs, which we refer to as 'multiplex therapy'.

We plan to expand the ImmunoBank to broaden the reach of multiplex TCR-T therapy for the treatment of solid tumors.

• Leverage our proprietary platform technologies to expand 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.

To ensure that the antigens identified are clinically relevant, we use TCRs from tumor samples of patients with exceptional responses to immunotherapy.

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

We continue to prioritize expanding the ImmunoBank with TCRs for additional targets as well as multiple common HLA types for each target, thus enabling us to address tumor heterogeneity and resistance that may arise from target loss or HLA loss.

• Maintain manufacturing capabilities.

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

For our TCR-T 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 our clinical programs in both heme malignancies and solid tumors through Phase 2 clinical trials.

For our TCR-T therapy product 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 believe provides sufficient capacity to support our clinical programs in both heme malignancies and solid tumors.

Additionally, we have engaged a global CDMO with commercial capabilities to further increase manufacturing capacity for both the heme and solid tumor programs and prepare for potential commercial manufacturing.

The CDMO is on track to support clinical manufacturing of the heme program in the second half of 2025.

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

By introducing the gene for CD8α/β along with the TCR gene, we are able to engineer both cytotoxic and helper T cells, which we believe has the potential to improve responses to TCR-T therapy in the clinic compared to engineering cytotoxic T cells alone.

We are also adding a DN-TGFβRII to T cells, which enables them to proliferate despite the presence of TGFβ in the hostile tumor microenvironment.

We are also adding DN-TGFβRII to T cells, which enables them to proliferate despite the presence of TGFβ in the hostile tumor microenvironment.

This has the potential to enhance T cell persistence.

With the FDA clearance of our IND applications for TSC-100, TSC-101, and our seven IND applications for our solid tumor program, including our primary IND application, T-Plex, we consider our approach to be validated.

Having treated over 30 patients with six different TCR-T candidates across both heme and solid tumor malignancies, we consider our approach to be validated.

• Develop next generation T cell engineering capabilities .

Our long-term vision is to develop off-the-shelf products, either through allogeneic T-cell engineering or in vivo engineering, and provide customized multiplexed TCR-T therapy to patients with a wide range of malignancies.

Our long-term vision is to develop off-the-shelf products, either through allogeneic T-cell engineering or in vivo engineering, and provide customized multiplex TCR-T therapy 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 alternative modalities.

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To date, we have a research collaboration and license agreement with Amgen to identify the antigens recognized by T cells in patients with Crohn’s disease.

Under the terms of the agreement, TScan received a $30 million upfront payment and is eligible to earn success-based milestone payments of over $500 million, based upon the achievement of certain development and commercial milestones as well as tiered single-digit royalty payments on net sales of products development from the collaboration.

Under the terms of the agreement, TScan received a $30.0 million upfront payment and is eligible to earn success-based milestone payments of over $500 million, based upon the achievement of certain development and commercial milestones as well as tiered single-digit royalty payments on net sales of products developed

from the collaboration.

Amgen will evaluate a variety of modalities to create therapeutics based on targets discovered by TScan and will retain all global development and commercial rights to such therapeutics.

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.

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

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

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Successes in immuno-oncology came initially from the approval of immune checkpoint inhibitors and more recently from the development of cellular therapies, such as CAR-T and TIL therapies.

These therapies all harness the power of cytotoxic T cells in fighting both hematologic malignancies and solid tumors.

These therapies all harness the power of cytotoxic T cells in fighting both heme malignancies and solid tumors.

Although these therapies have demonstrated compelling efficacy, they are only effective in a subset of patients.

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Helper T cells, which express the CD4 co-receptor, function by providing signals to other immune cells for activation and recruitment.

Cytotoxic T cells, which express the CD8 co-receptor, function by killing any cells in the human body that are expressing unnatural proteins, including proteins that are not expressed in normal tissue, proteins that arise from mutated genes, or proteins derived from

By definition, tumor cells are abnormal and make a wide variety of unnatural proteins.

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If the patient’s TILs do not have appropriate anti-cancer specificities or if their anti-cancer TILs cannot be adequately expanded ex vivo , the therapy is unlikely to be effective.

A different approach that has proven effective in certain hematological malignancies is to identify targets that are highly expressed on the surface of tumor cells, such as CD19.

A different approach that has proven effective in certain heme malignancies is to identify targets that are highly expressed on the surface of tumor cells, such as CD19.

Antibody fragments that recognize these targets are used to create an artificial construct that links the antibody to key signaling elements required for T cell activation.

The resulting CAR is incorporated genetically into a

patient’s T cells, thereby redirecting those cells to recognize and fight the patient’s cancer.

The resulting CAR is incorporated genetically into a patient’s T cells, thereby redirecting those cells to recognize and fight the patient’s cancer.

Although CAR-T therapies have been highly effective in certain tumor types, leading to multiple approved products, the benefit of these therapies and the addressable cancer indications have been limited by several factors.

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Second, CAR-T cells rely on antibody fragments that recognize cell-surface proteins, precluding intracellular proteins as potential targets.

Third, CAR-T therapies generally do not efficiently penetrate solid tumors, which to date has limited their applicability to hematologic malignancies.

Third, CAR-T therapies generally do not efficiently penetrate solid tumors, which to date has limited their applicability to heme malignancies.

In contrast to CAR-T therapies, naturally occurring TCRs offer two important benefits compared to antibody-containing artificial receptors.

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As such, they are optimized to stimulate the T cell appropriately when they engage their targets on a tumor cell.

An appropriately stimulated T cell will not only kill the tumor cell, but also produce cytokines that stimulate other immune cells and make copies of itself, or proliferate, to further augment the immune response.

An appropriately stimulated T cell will not only kill the tumor

cell, but also produce cytokines that stimulate other immune cells and make copies of itself, or proliferate, to further augment the immune response.

Balancing all the cellular responses of a T cell is something that has been finely tuned over millions of years of evolution and is best mediated by naturally occurring TCRs, rather than by artificial constructs.

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We believe TCR-T therapy combines the benefits of TIL and CAR-T therapies while uniquely addressing their key limitations, as shown below.

Reprogramming T cells with proven, highly effective TCRs has the potential to comprehensively treat all cancer patients

The development of TCR-Ts requires three key prerequisites:

Building on the Remarkable Success of Immunotherapy

The development of TCR-T therapy product candidates requires three key prerequisites:

(i) an effective anti-cancer TCR;

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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 expanding 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 responding to immunotherapy agents.

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

This provides us with a novel TCR/target pair that can be developed into a TCR-T candidate.

The advantage of our approach is that when we identify a new target, we know the target is immunologically relevant – the human immune system has already used that target to recognize and fight cancer.

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

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 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 the ImmunoBank.

Our Proprietary Target and TCR Discovery Process

We have built and are expanding the ImmunoBank with the goal of delivering customized multiplex TCR-T therapy to a wide range of patients with cancers.

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-Ts 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.

We are developing TCR-T therapy product candidates 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.

Such patients will first have their tumors undergo HLA typing and testing for the presence of tumor-specific targets.

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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 therapies to more patients, where each

patient’s T cells are engineered with multiple TCRs that are matched to their specific tumor and HLA type.

We believe the continued expansion and diversification of the ImmunoBank will enable us to deliver customized multiplexed TCR-T therapies to more

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 application for the simultaneous administration of different TCRs, as well as secondary IND applications for the first six 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.

The FDA's clearance of our T-Plex IND application for the simultaneous administration of different TCRs, as well as secondary IND applications for the first seven 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, multiplex therapies to patients.

Once the T cells are engineered with a combination of the most relevant TCRs, they will be transported back to the treatment facility 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.

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

Our Patient Treatment and Manufacturing Process

Key Features of Our Approach

We believe there are three key advantages to our approach:

• Our TCR-Ts are based on highly active TCRs that are clinically relevant.

• Our TCR-T therapy product candidates are based on highly active TCRs that are clinically relevant.

Many other approaches to T cell therapy rely on specifically expanding T cells that are already present in the patient.

Our platform analyzes anti-cancer T cells from a wide variety of patients who are responding to immunotherapy in order to find the most active and clinically relevant TCRs against each target.

We believe that we can develop TCR-Ts for a wide range of patients, including those who do not have T cells that efficiently recognize their cancers.

• Our TCR-Ts are designed to be used in combination with each other.

We are expanding 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 that we can develop TCR-T therapy product candidates for a wide range of patients, including those who do not have T cells that efficiently recognize their cancers.

• Our TCR-T therapy product candidates are designed to be used in combination with each other.

We have built and are expanding the ImmunoBank of TCRs to allow for multiplex TCR-T therapy, which has the potential to address the heterogeneous nature of solid tumors and address 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 development to date.

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

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We have built 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 administration to patients.

Our proprietary platform is designed to:

(i) discover anti-cancer TCRs from patients with exceptional responses to immunotherapy;

(ii) determine novel targets of clinically relevant TCRs;

(iii) discover novel TCRs that recognize clinically validated targets;

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

(v) multiplex treatments through inclusion of clinically relevant targets with HLA type to customize treatments and (vi) manufacture TCR-Ts efficiently and consistently without the use of viral vectors using T-Integrate.

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

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

TargetScan—Identification of Novel Targets of Clinically Active TCRs

At the core of our proprietary platform is our TargetScan technology that enables us to identify the natural target of a TCR using an unbiased, genome-wide, high-throughput screen.

We have developed this technology to be extremely versatile and applicable across multiple therapeutic areas, including cancer, autoimmune disorders, and infectious diseases.

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 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.

If a T cell recognizes the peptide-MHC complex on a target cell, it attempts to kill the target cell, thereby activating a proprietary fluorescent reporter in the target cell.

By isolating fluorescent target cells and sequencing their

expression cassettes, TargetScan reveals the natural target(s) of the T cell, as shown below.

This technology was published as a feature article in Cell in 2019.

Overview of Our Proprietary TargetScan Technology

Central to this technology is the library of protein fragments used for any given TargetScan screen.

Our proprietary libraries comprise hundreds of thousands of specific sequences that collectively include most or all of the targets that a TCR could potentially recognize.

For example, our current Oncology Target Discovery Library (version 3.0) comprises of 700,000 clones, each expressing a unique protein fragment.

Collectively, these fragments span every human protein encoded in the human genome, along with all single nucleotide polymorphisms, or SNPs, which are single amino acid variations in naturally occurring proteins, observed at over 1% frequency in the human population.

In addition, the library includes elements that are specific to cancer cells, which are particularly interesting to us as potential targets:

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.

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

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

SafetyScan—Elimination of Off-Target Activity

SafetyScan is designed to identify potential off-target interactions of a TCR and eliminate those TCR candidates that cross-react with proteins expressed at high levels in critical organs.

We believe this will allow us to reduce the risk and enhance the potential safety profile of our TCR-T candidates early in development before we initiate clinical trials.

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

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.

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.

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.

Importantly, this includes off-targets that may not be identified through standard bioinformatics or in- vitro tissue assays.

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.

Using our TargetScan technology, we have identified approximately 200 novel antigens as targets of tumor infiltrating T cells from patients who are 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 we have also already identified highly active TCRs that recognize these targets.

ReceptorScan identifies ultra-high affinity, naturally occurring TCRs with low risk of off-target effects

T-Integrate—Genetic Engineering of T Cells Using Transposons

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

To enable the rapid, cost-effective, and consistent manufacturing for a variety of selected 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 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:

(1) delivering DNA encoding the TCR into the nucleus of a T cell and (2) integrating that DNA into the genome of the T cell.

These two steps are often accomplished through the use of retroviral vectors, such as lentivirus, by packaging RNA encoding the TCR into lentiviral particles, which are then used to infect T cells.

Although effective, manufacturing lentiviral particles is time-consuming, costly, and often highly variable.

In addition, each new TCR requires extensive process development, as the TCR sequence affects the efficiency with which it is packaged into the lentivirus.

As a more efficient and reproducible alternative to lentivirus, we have developed T-Integrate to genetically engineer T cells using a transposon/transposase system, as shown in the graphic below.

In this system, DNA encoding the TCR is manufactured as a Nanoplasmid and enables DNA delivery using a smaller plasmid footprint.

The Nanoplasmid, together with an mRNA sequence encoding a transposase enzyme, is introduced into the T cell by electroporation.

After the T cell translates the mRNA into protein, the transposase enzyme inserts the TCR sequence from the Nanoplasmid into the genome of the T cell.

This system is highly reproducible, as the only required components are a Nanoplasmid, which is different for each TCR product, and an mRNA, which is constant for all TCR products.

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

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

We have successfully manufactured TSC-100 and TSC-101 and dosed patients in our hematologic malignancies program.

The FDA has cleared seven IND applications for our solid tumor program, including our primary IND application, T-Plex, which supports the simultaneous administration of multiple TCRs to create customized multiplexed TCR-T candidates, as well as IND applications for TSC-200-A0201 (HPV16, HLA-A*02:01), TSC-201-B0702 (MAGE-C2, HLA-B*07:02), TSC-203-A0201 (PRAME, HLA-A*02:01), TSC-204-A0201 (MAGE-A1, HLA-A*02:01), TSC-204-C0702 (MAGE-A1, HLA-C*07:02), and TSC-204-A0101 (MAGE-A1, HLA-A*01:01).

Our T-Integrate Manufacturing Platform

Our transposon vector includes both the beta and alpha chains of the TCR under the control of a strong promoter.

This is designed to ensure that high levels of the TCR are produced on the surface of the T cells and that the TCRs that are normally expressed in the patient’s or donor’s T cells, or the ‘endogenous’ TCRs, are suppressed.

We have also introduced specific alterations in the constant region of the TCR to further augment its stability.

In addition to the TCR, our transposon construct includes genes encoding the alpha and beta chains of the cell-surface protein CD8.

CD8 forms a complex with the TCR and is necessary for the TCR to recognize its target on tumor cells.

Including the CD8 co-receptor in our construct enables us to genetically reprogram both major types of T cells:

cytotoxic T cells that naturally make their own CD8, and helper T cells that do not make CD8.

Our final TCR-Ts are a mixture of both cytotoxic and helper T cells that have been reprogrammed to recognize and eliminate tumor cells expressing the relevant targets.

We also included a short peptide tag at the beginning of CD8α in our construct.

This tag does not interfere with the function of CD8α but provides a way to easily purify the engineered T cells during our manufacturing process.

We are also enhancing our T cell therapies with the addition of DN-TGFβRII to overcome the immunosuppressive tumor microenvironment.

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

Construct of our TCR-Ts

Another important advantage of T-Integrate, our manufacturing platform, is that its greater carrying capacity than the commonly used lentiviral approach enables us to introduce additional genes that augment T cell function along with the gene that encodes the TCR itself.

As our programs advance, we intend to introduce additional elements to our products with the goal of further improving their performance in the solid tumor setting, including features designed to increase the penetration of our T cells into solid tumors, with the aim of keeping our T cells active for a longer time and rendering our T cells more impervious to the hostile tumor microenvironment.

Our Hematologic Malignancies Program

We are developing our hematologic malignancies program to treat patients with AML, MDS, or ALL who are undergoing allogeneic HCT.

Our Heme Malignancies Program

We are developing our heme malignancies program to treat patients with AML, MDS, or 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.

Our program is based on the well-established observation that patients who are mismatched with their donors for minor histocompatibility antigens such as HA-1 or HA-2, and naturally mount a T cell response against those antigens, show significantly lower relapse rates following HCT.

Our program is based on the well-established observation that patients who are mismatched with their donors for minor histocompatibility antigens, or miHAs, such as HA-1 or HA-2, and naturally mount a T cell response against those antigens, show significantly lower relapse rates following HCT.

By developing TSC-100 and TSC-101, TScan aims to recreate this natural graft versus leukemia response to prevent relapse in patients undergoing HCT.

Minor histocompatibility antigens like HA-1 and HA-2 are distinct from other cancer-associated antigens such as WT1 previously targeted by TCR-Ts in hematologic malignancies.

As shown below, cancer-associated antigens like WT1 have low and heterogenous expression and were previously selected so that normal blood cells in the patient would be relatively spared.

WT1-targeted TCR-Ts proved to have relatively poor efficacy in patients with AML, potentially due to the rapid emergence of resistant tumor cells that had lacked WT1 expression and thus escaped killing by engineered T cells.

HA-1 and HA-2 in contrast have high and homogenous expression (see below), making it less likely for tumors cells to escape due to low antigen expression.

While HA-1 and HA-2 are also expressed in normal blood cells, treating HA-1/HA-2 positive patients who receive stem cell transplantation from donors who are negative for HA-1/HA-2, ensures that the engineered T cells selectively eliminate all the patient’s blood cells, malignant, pre-malignant or normal, while sparing donor-derived normal blood cells.

We plan to further expand this program with the addition of TCRs targeting additional antigens across different HLA types.

For example, TSC-102-A0301, a TCR-T therapy product candidate targeting an HLA-A*03:01-restricted epitope on CD45, is currently in IND-enabling activities.

Minor histocompatibility antigens like HA-1 and HA-2, and lineage-specific antigens like CD45, are distinct from other cancer-associated antigens such as WT1 previously targeted by TCR-Ts in heme malignancies.

As shown below, cancer-associated antigens like WT1 have low and heterogenous expression and were previously selected so that normal blood cells in the patient would be spared.

WT1-targeted TCR-Ts proved to have relatively poor efficacy in patients with ALL and AML, potentially due to the rapid emergence of resistant tumor cells that lacked WT1 expression and thus escaped killing by engineered T cells.

HA-1, HA-2, and CD45, in contrast, have high and homogenous expression, making it less likely for tumors cells to escape due to low antigen expression.

Although HA-1, HA-2, and CD45 are also expressed in normal blood cells, treating patients who are positive for these antigens, but have undergone hematopoietic cell transplantation from donors who are negative, ensures that the engineered T cells selectively eliminate all the patient’s blood cells – malignant, pre-malignant, or normal – while sparing donor-derived normal blood cells.

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

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

Our Clinical Development Strategy for Multiple TCR-T Candidates

Background on Hematologic Malignancies

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

We are conducting a Phase 1 clinical trial of our lead TCR-T therapy product candidates, TSC-100 and TSC-101, in parallel, with patients 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, are eligible for enrollment, provided they are paired with donors who are negative for either the target antigen or the HLA-A*02:01 allele.

ALLOHA, a Multi-arm Phase 1 Trial for TSC-100 and TSC-101 in Subjects with AML, ALL, and MDS

Background on Heme Malignancies

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

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

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The patient then receives hematopoietic stem cells from an HLA-matched donor.

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.

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.

For example, patients with AML who receive HCT have a five-year post-transplant survival rate of up to 50%.

Approximately 8,000 allogeneic HCT procedures are performed yearly in the U.S., primarily in patients with AML, MDS, or ALL.

Approximately 7,350 allogeneic HCT procedures are performed yearly in the U.S.

in patients with AML, MDS, or ALL.

As a curative therapy for many hematologic malignancies, use of HCT has been steadily increasing over the last two decades, with increased use driven largely by increasing donor qualification, an increase in disease prevalence due to aging populations, and improved conditioning regimens permitting broader use in older and frailer patient segments.

As a curative therapy for many heme malignancies, use of HCT has been steadily increasing over the last two decades, with increased use driven largely by increasing donor qualification, an increase in disease prevalence due to aging populations, and improved conditioning regimens permitting broader use in older and frailer patient segments.

In addition, newer, more effective leukemia therapies continue to drive an increasing use of HCT in patients who previously failed to achieve proper remission prior to transplant.

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While loss of B cells does not generally lead to serious complications, toxicity on other normal myeloid blood cell types such as neutrophils would cause a life-threatening complication called febrile neutropenia in which bacterial infections occur due to the loss of neutrophils.

This is one reason why CAR-T therapies cannot be used in non-B cell hematologic malignancies such as myeloid leukemias and HCT remains the standard of care for those patients.

However, despite the increasing use of HCT and the resulting clinical benefits or cures, approximately 40% of the patients who receive HCT relapse, at which point there are limited treatment options, and the prognosis is very poor.

Clinical observations have shown that if the T cells of the donor recognize certain minor histocompatibility antigens, or miHAs, in the patient’s leukemia cells, such as proteins that have single amino acid differences between the patient and the donor, the T cells of the donor drive a specific graft vs.

This is one reason why CAR-T therapies cannot be used in non-B cell heme malignancies such as myeloid leukemias and HCT remains the standard of care for those patients.

However, despite the increasing use of HCT and the resulting clinical benefits or cures, approximately 40% of the patients who receive HCT relapse within two years, at which point there are limited treatment options, and the prognosis is very poor.

Clinical observations have shown that if the T cells of the donor recognize certain miHAs in the patient’s leukemia cells, such as proteins that have single amino acid differences between the patient and the donor, the T cells of the donor drive a specific graft vs.

leukemia, or GvL, effect, whereby the engrafted donor T cells detect remaining leukemia as foreign and eliminate the remaining disease.

As a result, the patient often experiences a long-term remission from their cancer, or even a complete cure.

the patient often experiences a long-term remission from their cancer, or even a complete cure.

If the miHAs are also expressed in non-hematopoietic tissues, the patient may develop graft vs.

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 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.

TSC-100 is an allogeneic, donor derived TCR-T 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.

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.

We selected TCR-100a based on its superior affinity, cytotoxic activity, and specificity compared to the others.

Our heme 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.

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

We selected this product candidate based on its superior affinity, cytotoxic activity, and specificity compared to the other potential candidates.

TSC-100 is designed to elicit an anti-tumor response in patients by targeting HA-1, which is present on malignant and normal blood cells of HA-1-positive patients but not on any of the new, donor-derived blood cells they receive from a donor who is either HA-1-negative or HLA-A*02:01-negative.

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.

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

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

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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.

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.

Because the patient’s new healthy blood cells are derived from the donor and are therefore either HA-1-negative or HLA-A*02:01-negative, we believe that TSC-100 should have minimal toxic side effects.

A summary of the treatment paradigm for TSC-100 is illustrated below.

TSC-100 Treatment Paradigm

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.

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To ensure that TSC-100 can 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.

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.

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.

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.

Like TSC-100, TSC-101 is an allogeneic, donor derived TCR-T 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.

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

HA-2, which is derived from the protein MYO1G, is another miHA that has been identified to be clinically relevant.

In patients who naturally develop HA-2-specific T cells, a GvL effect has been observed and these patients experience long-term remissions.

Using ReceptorScan, we have identified a highly active TCR, which we refer to as TCR-101a, that recognizes HA-2.

We are developing TSC-101 based on a highly active TCR we discovered that recognizes HA-2.

Unlike HA-1, the HA-2 antigen is highly prevalent, with approximately 95% of individuals in the U.S.

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However, as with HA-1, a specific HLA type, HLA-A*02:01, which is present in approximately 42% of individuals in the U.S., 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.

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.

Like TCR-100a, we used ReceptorScan to identify TCR-101a.

We screened approximately 237 million CD8+ cells from five healthy HA-2 negative donors and identified approximately 1,302 natural TCRs that recognize HA-2.

These were then narrowed down to 15 TCRs with the highest surface expression and greatest affinity for the HA-2 peptide.

We further evaluated the top five TCRs for off-target cross-reactivity against the entire human proteome using SafetyScan, identifying TCR-101a as the most active TCR with the lowest off-target activity and cleanest cross-reactivity profile against 108 other HLA alleles.

Finally, TSC-101, our TCR-T candidate which is T cells manufactured to express TCR-101a, was tested on a panel of normal cell types representing all vital organs and did not recognize any normal non-hematologic cell type.

In contrast, TSC-101 demonstrated efficient cell killing of both normal and malignant primary hematologic samples confirming a high degree of selectivity for hematologic cells.

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

Clinical Development Plan for Our Hematologic Malignancies Program

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.

A summary of the treatment paradigm for TSC-101 is shown below.

Patient Journey for TSC-101

TSC-102-A0301

Like TSC-100 and TSC-101, TSC-102-A0301 is an allogeneic, donor derived TCR-T therapy product candidate directed at eliminating residual cancer cells in patients with heme malignancies who are HLA-A*03:01-positive undergoing HCT using a donor who is HLA-A*03:01-negative.

CD45, which is derived from the protein PTPRC, is an antigen that has been identified to be clinically relevant.

For example, radiolabeled CD45 is in clinical trials for relapsed AML, and a CAR-T product candidate targeting CD45 with epitope-edited HSCs is in pre-clinical development.

We are developing TSC-102-A0301 based on a highly active TCR we discovered that recognizes a CD45 antigen presented on HLA-A*03:01.

TSC-102-A0301 is currently in IND-enabling activities.

The CD45 antigen is expressed on all nucleated cells of hematopoietic origin.

As with TSC-100 and TSC-101, a specific HLA type, HLA-A*03:01, which is present in approximately 22% individuals in the U.S.

is required to display the CD45 antigen on the cell surface for recognition by TSC-102-A0301.

HLA-A*03:01 negative donors are straightforward to identify and should be available to most patients who undergo HLA half-matched, or haploidentical, transplantation using family members as donors.

HLA-A*03:01 negative donors can also be mismatched unrelated donors readily identified through donor registries such as the National Marrow Donor Program.

Having such donor options thus enables virtually all HLA-A*03:01 positive patients to potentially qualify for treatment with TSC-102-A0301.

Clinical Development Plan for Our Heme Malignancies Program

Background on Types of HCT

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Lower-intensity regimens are called reduced-intensity conditioning, or RIC, and are better tolerated, but are associated with higher relapse rates.

TSC-100 and TSC-101 are both designed to substantially reduce relapse rates, and we are enrolling patients who are eligible for RIC-based HCT with the goal of improving clinical outcomes for these patients.

Our heme malignancies TCR-T therapy product candidates are designed to substantially reduce relapse rates, and we are enrolling patients into our ongoing Phase 1 clinical trial who are eligible for RIC-based HCT with the goal of improving clinical outcomes for these patients.

There are different types of donors who are eligible for allogeneic HCT procedures.

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and worldwide.

The use of haplos greatly expands the donor pool for patients undergoing HCT and provides patients with the optionality to choose donors who are mismatched on specific HLA types, such as A*02:01, as opposed to being mismatched on certain minor antigens, such as HA-1 or HA-2.

We are developing TSC-100 and TSC-101 with a specific focus on patients undergoing haplo donor transplantation with donors who are negative for either the miHA or the specific HLA type.

The use of haplo greatly expands the donor pool for patients undergoing HCT and provides patients with the optionality to choose donors who are mismatched on specific HLA types, such as A*02:01, as opposed to being mismatched on certain minor antigens, such as HA-1 or HA-2.

We are developing our product candidates with a specific focus on patients undergoing haplo donor transplantation with donors who are negative for either the miHA or the specific HLA type.

We believe the engineered donor T cells will recognize any residual leukemia cells, which are target-positive, in the patient and prevent relapse with the potential to promote complete cures.

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.

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 expect that these product candidates should have minimal toxic side effects.

Phase 1 Clinical Trial

The clinical studies for TSC-100 and TSC-101 are well underway, 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.

We are currently dose escalating both treatment arms and are currently treating patients at the third and final dose level.

The clinical studies for TSC-100 and TSC-101 are well underway, 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 AML, MDS, and ALL that are undergoing HCT following RIC.

We are currently treating patients at the third and final dose level.

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

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.

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 trial towards a potential future biologics license application, or BLA, filing.

Multi-Arm Phase 1 Clinical Trial Design

Initial clinical data

In February 2024 we reported updated results on the first 14 patients enrolled in our ongoing Phase 1 hematologic malignancies study, which we presented at the 2024 Tandem Meetings:

Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT ® ) and the Center for International Blood and Marrow Transplant Research (CIBMTR ® ).

Eight patients were enrolled in the treatment arms, and six patients were enrolled in the control arm.

A total of four patients were treated with TSC-100, one with T-ALL, two with AML, and one with MDS, and four patients were treated with TSC-101, one with TP53-mutated MDS, one with AML and two with B-ALL.

In both the TSC-100 and TSC-101 treatment arms, all patients (8/8) achieved complete donor chimerism, associated with a favorable prognosis.

One AML patient was MRD-positive following HCT, converted to MRD-negative following treatment with TSC-101, and maintained MRD-negative status, with the most recent measurement at day 180 post-transplant.

The six control-arm patients, three with MDS and three with AML, were enrolled and received standard of care consisting of HCT alone.

One TP53-mutated MDS control-arm patient evolved with MRD positivity and worsening mixed chimerism, ultimately experiencing disease relapse approximately six months after transplantation and unfortunately succumbed to the relapse approximately nine months after transplant.

Additionally, one MDS patient in the control arm had a clinical relapse approximately five months after transplantation, and one MDS patient in the control arm developed worsening mixed chimerism that prompted early termination of immunosuppression resulting in complete donor chimerism.

Two of the six patients in the control arm achieved complete donor chimerism following HCT.

Clinical data

In December 2024 we reported updated results from the ongoing Phase 1 ALLOHA trial, which we presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition.

At that time, 38 patients had been enrolled in the trial and undergone HCT, with 26 in the treatment arm and 12 in the control arm.

The key endpoints in the trial are safety and efficacy, with exploratory endpoints of donor chimerism and MRD.

As shown below, event-free survival favored the treatment arm (HR=0.30;

P=0.04) and early trends suggested a lower probability of relapse (HR=0.28;

As of the latest data cut (December 2, 2024, shown below), 2 of 26 (8%) of treatment-arm patients relapsed compared to 4 of 12 (33%) control-arm patients.

One treatment-arm relapse and subsequent mortality occurred in a very high-risk patient who was taken to transplant without first achieving complete remission, and the other was an extramedullary relapse in the patient's central nervous system with no evidence of systemic relapse.

Median time to relapse was not evaluable in the treatment-arm versus 160 days in the control arm.

Eight of 38 (21%) patients in the study had TP53 mutations, with 6 cases in the treatment-arm and 2 cases in the control arm.

Of the 4 patients in the treatment arm with these mutations who received TCR-T cell infusions, none has relapsed, and one patient has now been relapse-free for 22 months.

Of the two patients in the control arm with mutated TP53, both relapsed within 6 months of transplant and died shortly thereafter.

TSC-100 and TSC-101 infusions were generally well-tolerated at all three dose levels with no dose-limiting toxicities.

Observed adverse events were similar across the treatment and control arms and were generally consistent with post-HCT adverse events.

TSC-100 and TSC-101 TCR-T cells were detected at all time points in all treated patients, including those who have been on study for over a year, with clear evidence of a dose-persistence relationship (shown below).

Anticipated timeline

We have now successfully manufactured and dosed patients in both treatment arms of the Phase 1 clinical trial.

Patients have been enrolled up to the third and final dose level in both treatment arms with no dose limiting toxicities thus far, suggesting that the third and final dose level will likely become the recommended Phase 2 dose.

We expect to open expansion cohorts at this recommended Phase 2 dose level to further characterize safety and evaluate translational and efficacy endpoints in the third quarter of 2024.

Additionally, we plan to complete enrollment and report one-year clinical and translational data on initial patients in 2024 and report two-year prevention of relapse data in 2025.

We have now successfully manufactured our product candidates and dosed patients in both treatment arms of the Phase 1 clinical trial.

Patients have been enrolled up to the third dose level in both treatment arms with no dose limiting toxicities thus far, suggesting that the third dose level will likely become the recommended Phase 2 dose.

We have opened expansion cohorts at dose level 3 to further characterize safety and evaluate translational and efficacy endpoints.

We plan to continue development of TSC-101 only, as TSC-101 enables treatment of ~98% of patients with the HLA type A*02:01.

We expect to initiate a registrational trial for TSC-101, pending further feedback from regulatory authorities, in the second half of 2025.

We plan to present additional data from the Phase 1 trial by the end of the year, including two-year relapse data on the initial patients.

We also plan to file an IND application for TSC-102-A0301, a TCR-T therapy product candidate targeting an HLA-A*03:01-restricted epitope on CD45, in the second half of 2025.

Future market expansion opportunities

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First, only patients who achieve a clinical complete remission (CR) are referred for HCT since the relapse rates of patients not in CR are considered too high to effectively use HCT.

If HCT, combined with either TSC-100 or TSC-101, markedly reduces relapse rates, patients who do not achieve CR could possibly undergo HCT and

benefit from its curative potential.

If HCT, combined with either TSC-100 or TSC-101, markedly reduces relapse rates, patients who do not achieve CR could possibly undergo HCT and benefit from its curative potential.

This market expansion would require a separate clinical trial.

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If successful, this would further expand the curative potential of HCT combined with TSC-100 or TSC-101 therapy to older, frailer patients.

We could also expand the addressable market through the addition of TCRs for other HLA types, of which TSC-102-A0301 is an example of this approach.

A final market expansion opportunity could occur from the use of either TSC-100 or TSC-101 as a chemotherapy and radiation-free conditioning regimen for non-malignant diseases such as sickle cell anemia which are currently treated with HCT.

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Solid Tumor Program

We are developing a portfolio of autologous TCR-T candidates designed to be used in combination with each other to treat and eliminate solid tumors.

Our TSC-20X series of product candidates are designed to elicit an anti-tumor response in patients by targeting cancer-specific antigens in their tumor cells.

Our TCR-T 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.

We are developing a portfolio of autologous TCR-T therapy product candidates designed to be used in combination with each other to treat and eliminate solid tumors.

Our solid tumor product candidates are designed to elicit an anti-tumor response in patients by targeting cancer-specific antigens in their tumor cells.

Our TCR-T therapy product candidates include:

(i) well-recognized cancer targets that have demonstrated anti-tumor activity in clinical trials as well as 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.

Our six solid tumor TCR-T candidates include a combination of known targets, such as HPV16 for TSC-200, the previously undisclosed target MAGE-A4 for TSC-202, PRAME for TSC-203, and MAGE-A1 for TSC-204, as well as a novel TCR-T target that has not yet been tested in the clinic, MAGE-C2 for TSC-201.

To date, we have received FDA clearance for seven 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 candidates based on target and HLA expression.

Our seven solid tumor TCR-T therapy product candidates address known and novel targets, including HPV16 for TSC-200-A0201, MAGE-C2 for TSC-201-B0702, MAGE-A4 for TSC-202-A0201, PRAME for TSC-203-A0201, and MAGE-A1 for TSC-204-A0201, TSC-204-C0702, and TSC-204-A0101.

To date, we have received FDA clearance for eight 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 multiplex TCR-T therapy product candidates based on target and HLA expression.

The FDA has also cleared INDs for TSC-203-A0201 (PRAME, HLA-A*02:01);

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TSC-202-A0201 (MAGE-A4, HLA-A*02:01);

TSC-204-A0201 (MAGE-A1, HLA-A*02:01);

TSC-204-C0702 (MAGE-A1, HLA-C*07:02);

and TSC-204-A0101 (MAGE-A1, HLA-A*01:01).

We plan to further expand the ImmunoBank by filing INDs for additional TCRs throughout 2024.

In addition to our lead solid tumor TCR-T programs, we have identified about 200 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 have built the ImmunoBank, a repository 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 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 cancer.

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 simultaneously as a multiplexed TCR-T therapy.

Our Strategy to Treat Solid Tumors with Multiplexed TCR-T Therapy

TCR-Ts for the Treatment of Solid Tumors

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

We have built the ImmunoBank, a repository of highly active TCRs, to enable multiplex TCR-T therapy.

We are expanding the ImmunoBank with additional TCRs that recognize diverse targets and are associated with multiple HLA types to provide a broad array of therapeutic options for patients with various types of solid tumors.

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

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

We Are Building the ImmunoBank of TCRs to Enable Multiplex TCR-T Therapy

TCR-T Therapy Product Candidates for the Treatment of Solid Tumors

Immunotherapy has reshaped the treatment of solid tumors by demonstrating that tumor shrinkage, eradication, and long-term durable responses can be obtained by stimulating the patient’s own immune system to attack their cancer cells.

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By reprogramming the patient’s own T cells to recognize these targets, we believe that we can expand the dramatic responses observed with checkpoint inhibitor therapy to the patients for whom these therapies are ineffective.

Our solid tumor program is based on the premise that if we can understand how T cells naturally fight cancer, we can use this information to design life-changing TCR-Ts for virtually any patient with cancer.

Our discovery process begins with identifying patient T cells that are actively driving their clinical response to immunotherapy.

We then use TargetScan to determine the precise targets of these highly active TCRs.

Our discovery efforts are initially focused on patients with head and neck cancer who respond to checkpoint inhibitor therapy and patients with melanoma who respond to TIL therapy.

These cancers represent tumor types with a high degree of T cell infiltration and strong responses to immunotherapy, which provides us with clinically active T cells from which we can discover novel TCR/target pairs.

We have found that targets discovered in one type of cancer are often expressed in other cancers as well, enabling broader clinical development of our TCR-T candidates.

The tumor types we are focused on also express several known targets that were previously discovered from patient T cells.

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, 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

One of the ways we identify anti-cancer TCRs is by focusing on T cells that clonally expand in a tumor when the patient responds to checkpoint inhibitor therapy.

Some of this work is being performed under collaborative research agreements with various academic institutions.

Using single cell sequencing, our collaborators determined the TCR sequences of thousands of T cells in the tumors of patients with head and neck cancer before and after immunotherapy.

This analysis also revealed the frequency of each T cell clone in the tumor samples.

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.

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

clinical response.

An illustrative example of T cell sequencing data from one patient with head and neck cancer who had a complete response to immunotherapy can be found below.

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

Novel Targets Identified from Patients with Melanoma

Another approach we use to identify clinically relevant anti-cancer T cells is to analyze T cells from patients with melanoma who respond to TIL therapy.

Using single cell sequencing, we determine the TCR sequences of the T cells in the responding patient’s TIL therapy product and focus on the most abundant T cell clones.

We have found that TIL therapy products are often dominated by as few as two or three clones, further increasing our confidence that these TCRs played a causal role in fighting the patient’s cancer.

To increase the throughput of our discovery efforts, we have used TargetScan in a more directed manner to screen sub-libraries of protein fragments that focus on particular classes of tumor antigens.

For example, we built a sub-library that focuses on cancer/testis antigens, or CTAs, which are genes that typically play a role in embryonic development but are not expressed in any adult tissues other than testes.

T cells do not infiltrate testes and cells in the testes have very low levels of MHC proteins, making testes an immune-privileged site that will not be targeted by engineered T cells in the context of cell therapy.

CTA genes are frequently found to be expressed in tumor cells and often play a role in causing cancer.

Several well-recognized targets in development for TCR-T therapy are CTAs, including NY-ESO-1 and MAGE-A4.

We are focused on the discovery of novel targets within this class of antigens and have built a TargetScan library comprising 40,000 fragments that cover 1,600 CTA genes.

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

In a single screen, we identified two TCR/target pairs that recognize CTAs, including the antigen target for one of our lead solid tumor product candidates, TSC-201, which we recently disclosed as MAGE-C2, and TSC-202, which we recently disclosed as MAGE-A4.

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.

We found that TSC-201 (MAGE-C2) 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, MAGE-C2 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, and head and neck cancer.

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

As shown below on the left, when T cells expressing the TCR that recognizes MAGE-C2 are cultured with melanoma cell lines that naturally express different levels of MAGE-C2, such as A101D and SKMEL5, the degree to which the T cells get activated correlates with the expression level of MAGE-C2 in the melanoma cells.

In addition, the T cells kill melanoma cells expressing high levels of MAGE-C2, as shown below on the right but do not kill cells that express low levels of MAGE-C2, which highlights the selectivity of the TCR for MAGE-C2.

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

When the TCR that recognizes MAGE-C2 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 interaction 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.

Although the TCR recognizes target cells overexpressing protein fragments containing this off-target antigen, it does not recognize cells expressing the full-length protein at normal levels.

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.

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.

Ultimately, we believe this strategy has the potential to enable multiplexed TCR-T therapy in which a patient is treated with more than one TCR for the same target protein, presented on two different HLA alleles.

This approach could reduce the risk of resistance arising from loss, downregulation, or mutation of individual HLA genes.

TSC-20X Series

Our six clinical-stage solid tumor TCR-T candidates include a combination of known targets, such as HPV16 for TSC-200, MAGE-A4 for TSC-202, PRAME for TSC-203, and MAGE-A1 for TSC-204, as well as a target that is a novel antigen for TCR-T, MAGE-C2 for TSC-201.

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

In 2023, it is estimated that in the U.S., approximately 100,000 patients were diagnosed with melanoma, 67,000 with head and neck cancer, 200,000 with NSCLC, 14,000 with cervical cancer, 20,000 with ovarian cancer, and 18,000 with anogenital cancer.

We have advanced a combination of known and novel targets into clinical development, which is allowing us to use the product candidates targeting known antigens as backbones for our initial clinical trials evaluating multiplexed TCR-T therapy.

For example, we plan to evaluate TSC-203, which targets PRAME, a well-known and clinically validated tumor-specific protein, in combination with TSC-201 targeting MAGE-C2.

Our solid tumor program is designed to overcome key solid tumor resistance mechanisms of target loss and HLA loss.

Solid tumors are notoriously heterogeneous, with a solid tumor often expressing more than one target antigen.

We believe that by targeting multiple antigens expressed on in-tact HLAs, we will be able to drive deep and durable responses.

We continue to prioritize expanding the ImmunoBank with TCRs across different targets and HLA types to potentially enable customized multiplex TCR-T therapy.

Our Solid Tumor Product Candidates

Our seven clinical-stage solid tumor TCR-T therapy product candidates address known and novel targets, including E7 of HPV16 for TSC-200-A0201, MAGE-C2 for TSC-201-B0702, MAGE-A4 for TSC-202-A0201, PRAME for TSC-203-A0201, and MAGE-A1 for TSC-204-A0201, TSC-204-C0702, and TSC-204-A0101.

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

In 2024, it is estimated that in the U.S., approximately 190,000 patients were diagnosed with NSCLC, 14,000 with sarcoma, 58,000 with head and neck cancer, 14,000 with cervical cancer, and 28,000 with anal and genital cancer.

For example, we plan to evaluate TSC-203-A0201, which targets PRAME, a well-known and clinically validated tumor-specific protein, in combination with TSC-201-B0702 targeting MAGE-C2.

TSC-200 (HPV16)

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.

We are developing the TSC-200 series of product candidates as TCR-Ts targeting human papilloma virus, or HPV.

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 as 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.

In addition to head and neck cancers, HPV is found in more than 90% of cervical and anogenital cancers as well as over 60% of vaginal, vulval, and penile cancers.

Recent Phase 1 clinical data from the National Cancer Institute showed tumor regression with objective clinical responses in 50% of patients with metastatic HPV-positive cancers who were treated with a TCR-T candidate targeting HPV16, which we believe provides clinical support for the inclusion of an HPV16-targeting TCR-T, TSC-200-A0201, in our multiplexed TCR-T treatment strategy.

We have identified over a thousand TCRs that recognize HLA-A*02:01-specific antigens derived from HPV16 and have advanced TSC-200-A0201 (HPV16, HLA-A*02:01), into Phase 1 development.

In addition to head and neck cancers, HPV is found in more than 90% of cervical, anal and genital cancers.

Phase 1 clinical data from the National Cancer Institute showed tumor regression with objective clinical responses in 50% of patients with metastatic HPV-positive cancers who were treated with a TCR-T therapy candidate targeting E7 of HPV16, which we believe provides clinical support for the inclusion of an HPV16-targeting TCR-T, TSC-200-A0201, in our multiplex TCR-T treatment strategy.

We have advanced TSC-200-A0201 (HPV16, HLA-A*02:01) into Phase 1 development.

We also intend to extend our discovery efforts to include additional HPV16-derived antigens presented on other HLA types as the program advances, such as TSC-200-C0702 (HPV16, HLA-C*07:02), currently in discovery.

TSC-201 (MAGE-C2)

We are developing the TSC-201 series of candidates as TCR-Ts targeting melanoma-associated antigen C2, or MAGE-C2.

We are developing the TSC-201 series of TCR-T therapy product candidates as TCR-Ts targeting melanoma-associated antigen C2, or MAGE-C2.

We initially identified MAGE-C2 as the target of T cells from a melanoma patient responding to TIL therapy.

MAGE-C2 is a CTA that is exclusively expressed in testis and is not expressed in normal adult tissues.

MAGE-C2 is a cancer testis antigen, or CTA, that is exclusively expressed in testis and is not expressed in normal adult tissues.

The testis is an immune-privileged tissue and, as a result, we believe that targeting MAGE-C2 should not pose a significant safety concern.

In addition, MAGE-C2, which contributes to tumorigenesis by suppressing the cellular mechanisms responsible for controlling cell division, is selectively expressed across multiple different types of tumors, including approximately 50% of melanomas, approximately 25% of head and neck cancers, and approximately 50% of non-small cell lung cancers.

In addition, MAGE-C2, which contributes to tumorigenesis by suppressing the cellular mechanisms responsible for controlling cell division, is selectively expressed across multiple different types of tumors, including approximately 25% of head and neck cancers, and approximately 50% of non-small cell lung cancers.

Tumors expressing MAGE-C2 have been shown to be associated with metastasis and poor patient survival.

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TSC-202 (MAGE-A4)

We are developing the TSC-202 series of candidates as TCR-Ts targeting melanoma-associated antigen 4, or MAGE-A4.

We are developing the TSC-202 series of TCR-T therapy product candidates as TCR-Ts targeting melanoma-associated antigen 4, or MAGE-A4.

MAGE-A4 is a clinically established CTA that contributes to tumorigenesis by interfering with cell cycle arrest.

MAGE-A4 is expressed in 33% of cervical cancers enabling multiplexing with TSC-200, and MAGE-A4 is expressed in 50% of non-small cell lung cancers, 40% of head and neck cancers, and 30% of melanomas.

Using ReceptorScan, we have identified thousands of TCRs that recognize multiple HLA-A*02:01-specific epitopes derived from MAGE-A4 and have advanced one MAGE-A4 TCR-T, TSC-202-A0201, into lead optimization.

MAGE-A4 is expressed in 33% of cervical cancers enabling multiplexing with TSC-200, and MAGE-A4 is expressed in 50% of non-small cell lung cancers, 40% of head and neck cancers, and 20-70% of sarcomas depending on sub-type.

We have advanced one MAGE-A4 TCR-T therapy product candidate, TSC-202-A0201, into Phase 1 development.

TSC-203 (PRAME)

We are developing the TSC-203 series of candidates as TCR-Ts targeting Preferentially Expressed Antigen in Melanoma, or PRAME.

We are developing the TSC-203 series of TCR-T therapy product candidates as TCR-Ts targeting Preferentially Expressed Antigen in Melanoma, or PRAME.

Like MAGE-C2, PRAME contributes to tumorigenesis by suppressing cellular signals that control cell division, and higher expression levels of PRAME in tumors correlate with increased metastasis and poor patient outcomes.

PRAME is a CTA that, like MAGE-C2 and MAGE-A4, is absent in adult tissues except in the ovaries and testis.

Approximately 50% of NSCLCs, approximately 25% of cervical cancers, and approximately 90% of both melanomas and head and neck cancers express PRAME.

Moreover, PRAME expression is homogeneous within these tumors, which we believe makes it an attractive target for multiplexed TCR-T therapy.

Using ReceptorScan, we have identified thousands of TCRs across multiple PRAME-derived epitopes presented on HLA-A*02:01.

We are currently advancing three PRAME TCR-Ts;

Approximately 50% of NSCLCs, approximately 25% of cervical cancers, approximately 90% of head and neck cancers, and approximately 10-90% of sarcomas (depending on sub-type) express PRAME.

Notably, sarcoma subtypes that highly express PRAME also highly express MAGE-A4, making this an attractive indication for multiplex therapy.

We are currently advancing three PRAME TCR-T therapy product candidates:

TSC-203-A0201 (PRAME, HLA-A*02:01), currently in Phase 1 development;

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and TSC-203-A2402 (PRAME, HLA-A*24:02) currently in discovery.

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.

TSC-204 (MAGE-A1)

We are developing the TSC-204 series of candidates as TCR-Ts targeting melanoma-associated antigen 1, or MAGE-A1.

MAGE-A1 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.

We are developing the TSC-204 series of TCR-T therapy product candidates as TCR-Ts targeting melanoma-associated antigen 1, or MAGE-A1.

MAGE-A1 is a cancer/testis gene frequently overexpressed in a wide variety of solid tumors, including approximately 45% of head and neck cancers, 50% of cervical cancers and 50% of NSCLC.

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

Multiple different TCRs from this patient recognize a novel HLA-C*07:02-restricted epitope of MAGE-A1, and one of these TCRs is the basis of TSC-204-C0702 (MAGE-A1, HLA-C*07:02), currently in Phase 1 development.

In addition to this TCR-T candidate, we further expanded the TSC-204 series by using ReceptorScan to identify additional TCRs for MAGE-A1 epitopes presented on several other common HLA alleles to further expand the addressable patient population.

We are currently advancing five MAGE-A1

In addition to this TCR-T therapy product candidate, we further expanded the TSC-204 series by using ReceptorScan to identify additional TCRs for MAGE-A1 epitopes presented on several other common HLA alleles to further expand the addressable patient population.

We are currently advancing five MAGE-A1 TCR-T therapy product candidates:

TSC-204-A0201 (MAGE-A1, HLA-A*02:01), currently in Phase 1 development;

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and TSC-204-B0702 (MAGE-A1, HLA-B*07:02) currently in discovery.

In addition to our six lead solid tumor TCR-T candidates, we have identified approximately 200 novel antigens as targets of tumor infiltrating T cells from patients who are responding to immunotherapy using TargetScan.

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.

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.

We are continuing to leverage our platform technologies to expand patient eligibility for multiplex TCR-T therapy.

We plan to expand the ImmunoBank to address different HLA types to enable customized multiplex TCR-T therapy product 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-20X series of TCR-T candidates, we are evaluating multiple TCRs in parallel to determine the safety and preliminary efficacy of multiplexed TCR-T therapy.

The FDA has cleared our IND application for T-Plex, which serves as the primary IND application for our solid tumor program, enabling customized simultaneous administration 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 application and will reference the primary T-Plex IND application.

In addition to the T-Plex IND application, the FDA has cleared secondary IND applications for six TCR-T product candidates:

For the initial first-in-human studies for our solid tumor TCR-T therapy product candidates, we are evaluating multiple TCRs in parallel to determine the safety and preliminary efficacy of multiplex TCR-T therapy.

The FDA has cleared our IND application for T-Plex, which serves as the primary IND application for our solid tumor program, enabling customized simultaneous administration of TCR-T therapy product candidates to be administered to patients based on the targets and HLAs expressed in their tumors.

Specific TCRs for each patient are 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 therapy product candidate has been or will be filed as a secondary IND application and will reference the primary T-Plex IND application.

In addition to the T-Plex IND application, the FDA has cleared secondary IND applications for seven TCR-T therapy product candidates:

TSC-203-A0201 (PRAME, HLA-A*02:01);

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TSC-202-A0201 (MAGE-A4, HLA-A*02:01);

TSC-204-A0201 (MAGE-A1, HLA-A*02:01);

TSC-204-C0702 (MAGE-A1, HLA-C*07:02);

and TSC-204-A0101 (MAGE-A1, HLA-A*01:01).

We have initiated 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 cancer, cervical cancer, and anogenital 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 are currently enrolling patients in the screening protocol of this study, with patient dosing expected to commence in the first quarter 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 anogenital 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.

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 candidates in a multi-arm Phase 1 clinical trial, we plan to test our TSC-200 series of 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 simultaneous administrations in patients who are positive for the three respective targets.

Because the targets of TSC-201, TSC-202, TSC-203, and TSC-204 are also frequently expressed in melanoma and NSCLC, we will also explore various simultaneous administrations of these TCR-T candidates in patients with HPV-negative head and neck cancer, melanoma, and NSCLC.

We have initiated a multicenter Phase 1 clinical trial to evaluate the safety, preliminary efficacy, and feasibility of repeat dosing of multiplex TCR-T therapy.

We are enrolling patients with NSCLC, sarcoma, head and neck cancer, cervical cancer, and anal and genital cancer.

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

We are currently enrolling and treating patients in this study.

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

We will explore up to three-TCR simultaneous administrations in patients who are positive for the respective targets.

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

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

Dose Escalation Scheme Provides a Rapid Path to Multiplex TCR-T Therapy in Phase 1

Anticipated timeline

As we advance our solid tumor program, we anticipate submitting IND filings for additional TCRs throughout 2024.

As we continue to discover and validate TCR/target pairs, we aim to continue to file additional IND applications and introduce those solid tumor TCR-T 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 expanding the ImmunoBank to provide customized multiplexed TCR-Ts for virtually any patient with a solid tumor malignancy.

We plan to share initial data from the singleplex cohorts as well as initial multiplex data for our first simultaneous administrations of TCRs under T-Plex in 2024, with long-term duration of response data for multiplexed therapy anticipated in 2025.

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

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

We have successfully manufactured product candidates and infused patients with singleplex therapy and expect to dose our first multiplex patient in the first half of 2025.

We plan to report safety and response data for multiplex therapy in the second half of 2025.

ImmunoBank – Flexible Content for Diverse Platforms

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All of these engineering platforms require validated “content” – TCRs that recognize tumor-specific antigens on cancer cells without recognizing problematic off-targets.

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.

As we advance the ImmunoBank of TCRs through clinical development, we intend to continue to optimize our own manufacturing platform, in preparation for potential commercial manufacturing.

Ultimately, we aspire to build the largest collection of validated TCR “content” that can be used with a variety of T cell engineering platforms.

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We believe the discovery of these targets could enable the development of novel, more targeted therapeutic approaches to treat these diseases.

Our proprietary platform is designed to:

(i) discover anti-cancer TCRs from patients with exceptional responses to immunotherapy;

(ii) determine novel targets of clinically relevant TCRs;

(iii) discover novel TCRs that recognize clinically validated targets;

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

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

The central elements of our platform that we believe 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.

We have developed this technology to be extremely versatile and applicable across multiple therapeutic areas, including cancer, autoimmune disorders, and infectious diseases.

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

Using TargetScan, we have identified approximately 200 novel antigens as targets of tumor infiltrating T cells from patients who are actively responding to immunotherapy.

Two of our pipeline programs emerged from TargetScan:

TSC-201-B0702 (MAGE-C2, HLA-B*07:02) and TSC-204-C0702 (MAGE-A1, HLA-C*07:02), the latter of which was featured in the peer-reviewed journal Cell in 2022.

ReceptorScan.

T cells that recognize the target of interest proliferate

and are subsequently isolated based on their ability to recognize a fluorescently labeled version of the target.

We then use single cell sequencing to identify the specific TCR sequences that recognize the target.

Using ReceptorScan, we have identified our two lead TCR-T therapy product candidates, TSC-100 targeting HA-1 and TSC-101 targeting HA-2, as well as several other pipeline programs, including TSC-203-A0201 (PRAME, HLA-A*02:01), TSC-200-A0201 (HPV16, HLA-A*02:01), TSC-204-A0201 (MAGE-A1, HLA-A*02:01), TSC-204-A0101 (MAGE-A1, HLA-A*01:01), and TSC-202-A0201 (MAGE-A4, HLA-A*02:01).

SafetyScan is designed to identify potential off-target interactions of a given TCR and eliminate those TCR candidates that cross-react with proteins expressed at high levels in normal tissue.

We believe this will allow us to reduce the risk and enhance the potential safety profile of our TCR-T therapy product candidates early in development before we initiate clinical trials.

We are expanding the ImmunoBank, our diverse repository of therapeutic TCRs, to allow for multiplex TCR-T therapy, which has the potential to address the heterogeneous nature of solid tumors and address resistance developing due to loss of a single HLA haplotype.

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

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

Finally, we are expanding 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.

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

Our TCR-T therapy product candidates are manufactured using a transposon/transposase system, in which the DNA encoding the TCR is manufactured as a Nanoplasmid, a non-viral vector.

The Nanoplasmid, together with an mRNA sequence encoding a transposase enzyme, is introduced into the T cell by electroporation.

This system is highly reproducible, as the only required components are a Nanoplasmid, which is different for each TCR product, and an mRNA, which is constant for all TCR products.

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

We have a 51,100 square-foot GMP manufacturing facility (consisting of GMP clean room suites, laboratories, warehouse and office space) to manufacture clinical supply for our TCR-T therapy product candidates.

Our manufacturing platform has enabled us to efficiently develop and manufacture many different TCR-T therapy product candidates, allowing us to deliver customized multiplex therapy to patients with cancer.

We have successfully manufactured product candidates and have dosed patients in both our heme malignancies and solid tumor Phase 1 programs.

The FDA has cleared eight IND applications for our solid tumor program, including our primary IND application T-Plex, which supports the use of multiple TCR-T therapy product candidates to create customized multiplex TCR-T therapy, as well as IND applications for TSC-200-A0201 (HPV16, HLA-A*02:01), TSC-201-B0702 (MAGE-C2, HLA-B*07:02), TSC-202 (MAGE-A4, HLA-A*02:01), TSC-203-A0201 (PRAME, HLA-A*02:01), TSC-204-A0201 (MAGE-A1, HLA-A*02:01), TSC-204-C0702 (MAGE-A1, HLA-C*07:02), and TSC-204-A0101 (MAGE-A1, HLA-A*01:01), demonstrating our manufacturing capabilities.

To further increase our clinical manufacturing capacity and prepare for potential commercialization, we have engaged a global contract development and manufacturing organization, or CDMO, with worldwide commercial capabilities to support both the heme and solid tumor programs.

The CDMO is on track to support clinical manufacturing of the heme program in the second half of 2025.

License and Collaboration Agreements

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Amgen made an upfront payment of $30.0 million to us, and we are eligible to earn success-based milestone payments of over $500 million based upon the achievement of certain development and commercial milestones, as well as tiered single-digit royalty payments on net sales of products developed from the collaboration, subject to reductions set forth in the Amgen Agreement.

Collaboration and License Agreement with Novartis

On March 27, 2020, we entered into a Collaboration and License Agreement with Novartis Institutes for BioMedical Research, Inc.

(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 research funding totaling $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.

The ownership of inventions (and resulting patent rights) created in performance of the collaboration was determined by inventorship.

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

Our collaboration with Novartis concluded in March 2023.

Exclusive Patent License Agreement with BWH

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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.

In connection with the amendment 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.

We are obligated to use commercially reasonable efforts to develop and commercialize at least one product or process that practices the licensed patent rights and at least one therapeutic or diagnostic product or process directed to an epitope identified through practicing the licensed patent rights.

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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.

which epitopes are relevant to our platform for identifying potential TCR-Ts.

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 therapy product candidates.

Any sublicenses we grant to PHSA’s patent rights must also include a license of our own intellectual property;

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As a more operationally flexible and cost-efficient alternative to lentivirus, we have developed a manufacturing platform to genetically engineer T cells using a transposon/transposase system, which we refer to as T-Integrate.

We are designing our programs to use a transposon vector and corresponding transposase enzyme, which is derived from sfR fall armyworm, to deliver our TCRs into the genome of T cells.

We have designed our programs to use a transposon vector and corresponding transposase enzyme, which is derived from sfR fall armyworm, to deliver our TCRs into the genome of T cells.

Our transposon/transposase system effectively inserts our TCRs and other exogenous genes, such as CD8, at random locations in the genome.

The transposon will be delivered as a Nanoplasmid and has no antibiotic selection element, reducing the risk of inadvertent transmission of antibiotic resistance into T cells.

The transposase will be delivered as mRNA.

The transposon is delivered as a Nanoplasmid and has no antibiotic selection element, reducing the risk of inadvertent transmission of antibiotic resistance into T cells.

The transposase is delivered as mRNA.

mRNA is transiently expressed in the cell, reducing exposure of cells to prolonged transposase activity, which could result in multiple transposition events where the transposon would be moved around the genome.

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For clinical product manufacturing, we use single-use bag and tubing kits, supplies, and process reagents that are available from well-established vendors who specialize in supplying clinical grade reagents for the cell and gene therapy industry.

Our TCR-T candidates are released and characterized using well-developed analytical methods.

Our TCR-T therapy product candidates are released and characterized using well-developed analytical methods.

The final product used in clinical studies is cryopreserved, simplifying logistics and reducing risk of delivery failures to support patient dosing.

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We believe internalizing our manufacturing process and product testing enables us to better control this key aspect of clinical development and reduces the risk of program delay due to third-party reliance.

We expect to revisit our manufacturing process prior to commencing registrational trials and may use third-party contract manufacturing organizations (CMO) to increase our capacity in support of manufacturing product candidates for our registrational trials.

We continue to refine our manufacturing process to ensure it is commercially viable with focus on cost, consistency, and manufacturing success rate.

We have engaged a CDMO with global capabilities to support increased capacity and potential commercial manufacturing.

The CDMO is on track to support clinical manufacturing of the heme program in the second half of 2025.

We believe our novel and proprietary platform technologies, TargetScan, SafetyScan, and ReceptorScan, and our in-house cell therapy expertise constitute a meaningful competitive advantage in successfully developing novel and highly safe and effective treatments for cancer.

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We may also face competition from companies focused on other T cell therapies (e.g., TIL, CAR-T, gammadelta T cells) such as Iovance Biotherapeutics, Inc., Instil Bio, Inc., Achilles Therapeutics plc, 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., Regeneron Pharmaceuticals, Inc., through their acquisition of 2seventy Bio, Inc.’s research pipeline, AstraZeneca plc, through their acquisition of Gracell Biotechnologies, Inc., Legend Biotech Corporation, Autolus Therapeutics plc, Sana Biotechnology, 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.

For example, companies such as Takeda Pharmaceutical Company, Ltd., Sanofi S.A., through their acquisition of Kiadis Pharma N.V., Celyad, S.A., ImmunityBio, Inc., Celularity, Inc., Fate Therapeutics, Inc., and Nkarta, Inc.

For example, companies such as Takeda Pharmaceutical Company, Ltd., Celyad, S.A., ImmunityBio, Inc., Celularity, Inc., Fate Therapeutics, Inc., and Nkarta, Inc.

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

In addition, for our lead programs, TSC-100 and TSC-101, we may face competition from BlueSphere Bio, VOR Biopharma, Inc., IN8bio, 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, VOR Biopharma, Inc., IN8bio, Inc., Orca Biosystems, 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.

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In many cases, these drugs are administered in combination to enhance efficacy.

While our TCR-T candidates, if any are approved, may compete with these existing drugs and other therapies, to the extent they are ultimately used in combination with or as an adjunct to these therapies, our TCR-Ts may not be competitive with them.

While our TCR-T therapy product candidates, if any are approved, may compete with these existing drugs and other therapies, to the extent they are ultimately used in combination with or as an adjunct to these therapies, our TCR-T therapy product candidates may not be competitive with them.

Some of these drugs are branded and subject to patent protection, and others are available on a generic basis.

As a result, obtaining market acceptance of, and gaining a significant share of the market for, and commanding a certain price for any of our TCR-Ts that we successfully introduce to the market may pose challenges.

As a result, obtaining market acceptance of, and gaining a significant share of the market for, and commanding a certain price for any of our TCR-T therapy product candidates that we successfully introduce to the market may pose challenges.

In addition, many companies are developing new oncology therapeutics, and we cannot predict what the standard of care will be as our product candidates progress through clinical development.

We could see a reduction or elimination in our commercial opportunity if our competitors develop and commercialize drugs that are safer, more effective, have fewer or less severe side effects, are more convenient to administer, are less expensive, are more accessible, or receive a more favorable label than our TCR-T candidates.

Our competitors also may obtain FDA or other regulatory approval for their drugs more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

The key competitive factors affecting the success of all of our TCR-T candidates, if approved, are likely to be their efficacy, safety, convenience, accessibility, price, and the availability of reimbursement from government and other third-party payors.

The key competitive factors affecting the success of all of our TCR-T therapy product candidates, if approved, are likely to be their efficacy, safety, convenience, accessibility, price, and the availability of reimbursement from government and other third-party payors.

Intellectual Property

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We also seek to protect our proprietary rights by entering into confidentiality agreements and proprietary information agreements with suppliers, employees, consultants and others who may have access to our proprietary information.

The steps we have taken to protect our trade secrets, trademarks, patent applications and other intellectual property and proprietary rights may not be adequate, and third parties could infringe, misappropriate or misuse our intellectual property.

or misuse our intellectual property.

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

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provisional patent applications, multiple granted foreign patents, and more than 140 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 candidate), anti-HA-2 TCRs (including the TSC-101 TCR-T candidate), anti-HPV TCRs (including the TSC-200 TCR-T candidate), anti-MAGE-C2 TCRs (including the TSC-201 TCR-T candidate), anti-PRAME TCRs (including the TSC-203 TCR-T candidate), and anti-MAGE-A1 TCRs (including the TSC-204 TCR-T 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.

The claims of these patent applications are directed toward various aspects of our therapy candidates and research programs, including compositions of matter and uses thereof 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 product candidate), anti-HA-2 TCRs (including the TSC-101 TCR-T therapy product candidate), anti-HPV TCRs (including the TSC-200 TCR-T therapy product candidate), anti-MAGE-C2 TCRs (including the TSC-201 TCR-T therapy product candidate), anti-MAGE-A4 TCRs (including the TSC-202 TCR-T therapy product candidate), anti-PRAME TCRs (including the TSC-203 TCR-T therapy product candidate), and anti-MAGE-A1 TCRs (including the TSC-204 TCR-T therapy product 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 2045, in each case without taking into account any possible patent term adjustments or extensions and assuming that appropriate maintenance and governmental fees are paid.

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 international Patent Cooperation Treaty (PCT) applications began to enter the national and regional phases in May 2023.

The pending patent applications claim the benefit of priority from earlier-filed U.S.

priority provisional patent applications filed in 2020 and 2021.

We expect the issued Australian patents 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).

Heme Malignancies Program Product Patent Families

We have filed multiple patent families encompassing pending U.S.

and foreign patent applications covering aspects of our heme malignancies programs including claims to the composition-of-matter and uses thereof of TSC-100, TSC-101, and other anti-HA-1 and anti-HA-2 TCRs and related T cell therapies.

We expect the issued Australian and Singaporean patents, as well as any additional patents within these families, 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 and PCT international patent applications covering aspects of our solid tumor programs including claims to the composition-of-matter of anti-HPV, anti-MAGE-C2, anti-PRAME, anti-MAGE-A1 TCRs, and related T cell therapies.

The pending patent applications began to enter the national and regional phases in 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).

We have filed multiple patent families encompassing pending U.S.

and foreign patent applications covering aspects of our solid tumor programs including claims to the composition-of-matter of anti-HPV, anti-MAGE-C2, anti-MAGE-A4, anti-PRAME, anti-MAGE-A1 TCRs, and related T cell therapies.

We expect the issued Australian patents, as well as any additional patents within these families, 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 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 U.S., Australian, Canadian, European, Japanese, 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.

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).

We have filed multiple patent families encompassing pending U.S.

and foreign 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.

We expect the issued Australian and Democratic Republic of the Congo patents, as well as any additional patents within these families, 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.

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Platform Technology

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 have filed a patent family encompassing pending U.S.

and foreign patent applications covering aspects of our reporter-based T cell antigen screening platform.

In addition, we have filed several patent families encompassing pending U.S.

and foreign patent applications covering certain multiplexed TCR compositions and certain therapeutic methods thereof.

We expect any claims within these families, 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.

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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”.

For more information regarding the risks related to our intellectual property, please see “Item 1A.

Risk Factors—Risks Related to Our Intellectual Property” in this Annual Report.

Third-Party Intellectual Property Rights

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patent, one pending U.S.

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

patent application, a granted patent in each of Australia, France, Germany, Great Britain, Japan, Netherlands, Switzerland, and six foreign patent applications pending in Australia, Canada, China, Europe, Hong Kong, and Japan).

Any patents issuing from the U.S.

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

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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 of 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 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 U.S.

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

or IBCs, as set forth in the National Institutes for Health, or NIH, Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines.

In addition to the submission of an IND application to the FDA before initiation of a clinical trial in the U.S., certain human clinical trials involving recombinant or synthetic nucleic acid molecules are subject to oversight of institutional biosafety committees, or IBCs, 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:

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or (iii) molecules that result from the replication of those described in (i) or (ii).

Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an IBC, a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes

evaluation and assessment by an Institutional Biosafety Committee (IBC), a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such review may result in some delay before initiation of a clinical trial.

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Phase 3 trials consist of expanded multi-location testing for efficacy and safety to evaluate the overall benefit-to-risk index of the investigational drug in relationship to the disease treated.

The results of preclinical and human clinical testing are submitted to the FDA in the form of a BLA for approval to commence commercial sales.

In March 2022, the FDA released a final guidance, “Expansion Cohorts:

Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,” which outlines how drug developers can utilize an adaptive trial design in early stages of oncology drug development (i.e., the first-in-human clinical trial) to compress the traditional three phases of trials into one continuous trial called an expansion cohort trial.

Expansion cohort trials can potentially bring efficiency to drug development and reduce developmental costs and time.

All clinical trials must be conducted in accordance with FDA regulations, GCP requirements and their protocols in order for the data to be considered reliable for regulatory purposes.

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.

The results of preclinical and human clinical testing are submitted to the FDA in the form of a BLA for approval to commence commercial sales.

Our 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.

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Competitors may use this publicly available information to gain knowledge regarding the progress of development programs.

The BLA Approval Process

The Biologics License Application Approval Process

In order to obtain approval to market a drug in the U.S., a marketing application must be submitted to the FDA that provides data establishing to the FDA’s satisfaction the safety and effectiveness of the investigational drug for the proposed indication.

The application includes all relevant data available from pertinent non-clinical or preclinical studies and clinical trials, including negative or ambiguous

results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls and proposed labeling, among other things.

The application includes all relevant data available from pertinent non-clinical or preclinical studies and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls and proposed labeling, among other things.

Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including studies initiated by investigators that meet GCP requirements.

During the development of a new drug, sponsors are given opportunities to meet with the FDA at certain points.

These points may be prior to submission of an IND application, at the End-of-Phase 1 or 2, and before a BLA is submitted.

These points may be prior to submission of an IND application, at the End-of-Phase 1 or 2, and before a Biologics License Application, or BLA, is submitted.

Meetings at other times may be requested.

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The FDA has agreed to specific performance goals on the review of BLA’s.

Specifically, under the goals and policies agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, as amended, the FDA has 10 months, from the filing date, in which to complete its initial review of an original BLA and respond to the applicant, and six months from the filing date of an original BLA designated for priority review.

Specifically, under the goals and policies agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, as amended, the FDA has ten months, from the filing date, in which to complete its initial review of an original BLA and respond to the applicant, and six months from the filing date of an original BLA designated for priority review.

The review process may be extended by the FDA for three additional months to consider certain late-submitted information or information intended to clarify information already provided in the submission.

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Additionally, before approving a BLA, the FDA may inspect one or more clinical sites to assure compliance with GCP.

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

For a gene therapy product, the FDA also will not approve the product if the manufacturer is not in compliance with current Good Tissue Practice, or cGTP.

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.

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FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product, and FDA will not approve an application for a biosimilar or interchangeable product based on the reference biological product until 12 years after the date of first licensure of the reference product.

The FDA may approve multiple “first” interchangeable products so long as they are all approved on the same first day of marketing.

“First licensure” typically means the initial date the particular product at issue was approved in the U.S.

Date of first licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification

to the structure of the biological product that does not result in a change in safety, purity, or potency.

new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

Therefore, one must determine whether a new product includes a modification to the structure of a previously approved product that results in a change in safety, purity, or potency to assess whether the licensure of the new product is a first licensure that triggers its own period of exclusivity.

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If a PRV is received, it may be sold or transferred an unlimited number of times.

Congress has extended the PRV program through September 30, 2024, with the potential for PRVs to be granted through September 30, 2026.

Under current statutory sunset provisions, the FDA may award a PRV for an approved rare pediatric disease product application only if the sponsor has received rare pediatric disease designation for the drug by December 20, 2024, and after September 30, 2026, the FDA may not award any rare pediatric disease PRVs.

Congress may vote to reauthorize this program, but its future remains unknown at this time.

Expedited Development and Review Programs

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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 of the Code of Federal Regulations;

is intended to treat, modify, reverse, or cure a serious or life-threatening disease or

is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition;

and preliminary clinical evidence indicates that the product has the potential to address unmet medical needs for such disease or condition.

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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, the 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.

As a condition of approval, the 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 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.

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Post-Marketing Requirements

Following approval of a new product, a pharmaceutical company and the approved product are subject to continuing regulation by the FDA, including, among other things, monitoring and recordkeeping activities, reporting to the applicable regulatory authorities of adverse experiences with the product, providing the regulatory authorities with updated safety and efficacy information, product sampling and distribution requirements, and complying with promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling, or off-label use, limitations on industry-sponsored scientific and educational activities and requirements for promotional activities involving the internet.

the drug’s approved labeling, or off-label use, limitations on industry-sponsored scientific and educational activities and requirements for promotional activities involving the internet.

Although physicians may, in their independent professional medical judgment, prescribe legally available drugs for off-label uses, manufacturers typically may not market or promote such off-label uses.

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Prescription Drug Marketing Act, a part of the FDCA.

Additionally, under FDORA, sponsors of approved biologics must provide 6 months’ notice to the FDA of any changes in marketing status, such as the withdrawal of a drug, 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.

In the U.S., once a product is approved, its manufacturing is subject to comprehensive and continuing regulation by the FDA.

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Moreover, a third-party payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved.

Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.

Adequate third-party reimbursement may not be available to

enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.

Additionally, coverage and reimbursement for drug products can differ significantly from payor to payor.

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The containment of healthcare costs has become a priority of federal, state, and foreign governments, and the prices of drugs have been a focus in this effort.

Third-party payors are increasingly challenging the prices charged for drug products and medical services, examining the medical necessity, and reviewing the cost effectiveness of drug products and medical services, in addition to questioning

safety and efficacy.

If these third-party payors do not consider our products to be cost-effective compared to other available therapies, they may not cover our products after FDA approval or, if they do, the level of payment may not be sufficient to allow us to sell our products at a profit.

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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.

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.

Violations of this law are punishable by up to five years in prison, criminal fines, administrative civil money penalties, and exclusion from participation in federal healthcare programs.

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In addition, our future activities relating to the reporting of wholesaler or estimated retail prices for our products, the reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state, and third-party reimbursement for our products, and the sale and marketing of our products, are subject to scrutiny under this law.

The federal False Claims Act also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the federal False Claims Act and to share in any monetary recovery.

For example, pharmaceutical companies have been found liable under the Federal Civil False Claims Act in connection with their off-label promotion of drugs.

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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, 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.

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

Depending on the circumstances, failure to meet applicable regulatory requirements can result in significant criminal, civil and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in federal healthcare programs, such as Medicare and Medicaid, injunctions, recall or seizure of products, total or partial suspension of production, denial or withdrawal of product approvals, refusal to allow us to enter into supply contracts, including government contracts, contractual damages, reputational harm, administrative burdens, diminished

profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

We plan to develop a comprehensive compliance program that establishes internal controls to facilitate adherence to the law and program requirements to which we will or may become subject because we intend to commercialize products that could be reimbursed under a federal healthcare program and other governmental healthcare programs.

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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 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;

created a 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.

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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.

however legislation has been introduced in the U.S.

Congress that would, if enacted, reverse these payment reductions.

In addition to provider payment cuts under Medicare, the American Rescue Plan Act of 2021 also eliminated the statutory Medicaid drug rebate cap, previously set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

These laws and regulations may result in additional reductions in Medicare and other healthcare funding available for healthcare providers and may otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

• 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.

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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.

On the federal level, President Biden has issued multiple executive orders that have sought to reduce prescription drug costs.

In February 2023, HHS also issued a proposal in response to an October 2022 executive order from President Biden that includes a proposed prescription drug pricing model that will test whether targeted Medicare payment adjustments will sufficiently incentivize manufacturers to complete confirmatory trials for drugs approved through the FDA’s accelerated approval pathway.

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 (IRA) includes several provisions that may impact our business to varying degrees, including provisions that reduce the out-of-pocket spending cap for Medicare Part D beneficiaries from $7,050 to $2,000 starting in 2025, thereby effectively eliminating the coverage gap;

At a federal level, President Trump reversed some of President Biden’s executive orders including rescinding Executive Order 14087 entitled “Lowering Prescription Drug Costs for Americans." President Trump may issue new executive orders designed to impact drug pricing.

A number of these and other proposed measures may require authorization through additional legislation to become effective.

Congress and the Trump administration have indicated that they will continue to seek new legislative measures to control drug costs.

The Inflation Reduction Act of 2022 (IRA) includes several provisions that may impact our business to varying degrees, including provisions that reduce the out-of-pocket spending cap for Medicare Part D beneficiaries from $7,050 to $2,000 which began in 2025, thereby effectively eliminating the coverage gap;

impose new manufacturer financial liability on certain drugs under Medicare Part D, allow the U.S.

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It overhauls the system of approvals for clinical trials in the EU.

Specifically, the new legislation, which is directly applicable in all EU Member States (meaning that no national implementing legislation in each EU Member State is required), aims at simplifying and streamlining the approval of clinical trials in the EU.

For instance, the Clinical Trials Regulation provides for a streamlined application procedure via a single-entry point (instead of submitting applications separately to each national competent authority and ethics committee in the Member States in which the trial will be conducted) and strictly defined deadlines for the assessment of clinical trial applications.

Specifically, the Clinical Trials Regulation, which is directly applicable in all EU Member States (meaning that no national implementing legislation in each EU Member State is required), aims at simplifying and streamlining the approval of clinical trials in the EU.

For instance, it provides for a streamlined application procedure via a single-entry point (instead of submitting applications separately to each national competent authority and ethics committee in the Member States in which the trial will be conducted) and strictly defined deadlines for the assessment of clinical trial applications.

The Clinical Trials Regulation also makes it more efficient for EU Member States to evaluate and authorize applications together, via the Clinical Trials Information System.

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(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 are 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.

and (2) national marketing authorizations, which are issued by the competent authorities of the Member States and only authorize marketing in that Member State’s national territory and not the EEA as a whole.

The centralized procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, advanced therapy medicinal products (i.e., gene-therapy, somatic cell-therapy, and tissue-engineered medicines) and medicinal products containing a new active substance indicated for the treatment of HIV/AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune disorders and other immune dysfunctions and viral diseases.

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Under the above-described procedures, before granting the marketing authorization, the EMA or the competent authorities of the Member States of the EU make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety, and efficacy.

Now that the UK (which comprises Great Britain and Northern Ireland) has left the EU, Great Britain is no longer covered by centralized marketing authorizations (under the Northern Ireland Protocol, centralized marketing authorizations currently continue to be recognized in Northern Ireland).

On January 1, 2024, a new international recognition framework was put in place by the Medicines and Healthcare products Regulatory Agency, or MHRA, the UK medicines regulator, under which the MHRA may have regard to decisions on the approval of marketing authorizations made by the EMA and certain other regulators when considering an application for a Great Britain marketing authorization.

Regulatory exclusivity

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(i) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition;

(ii) either (a) such condition affects no

more than five in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify the necessary investment in its development;

(ii) either (a) such condition affects no more than five in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify the necessary investment in its development;

and (iii) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the product will be of significant benefit to those affected by the condition, as defined in Regulation (EC) 847/2000.

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Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated marketing authorization application assessment once a dossier has been submitted.

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.

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.

Where, during the course of development, a medicine no longer meets the eligibility criteria, support under the PRIME scheme may be withdrawn.

The aforementioned EU rules are generally applicable in the EEA.

All of the aforementioned EU rules are generally applicable in the EEA.

Reform of the Regulatory Framework in the European Union

The European Commission introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the EU for all medicines (including those for rare diseases and for children).

The European Commission has provided the legislative proposals to the European Parliament and the European Council for their review and approval.

In October 2023, the European Parliament published draft reports proposing amendments to the legislative proposals, which will be debated by the European Parliament.

The European Commission has provided the legislative proposals to the European Parliament and the European Council for their review and approval, and, in April 2024, the European Parliament proposed amendments to the legislative proposals.

Once the European Commission’s legislative proposals are approved (with or without amendment), they will be adopted into EU law.

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The UK formally left the EU on January 31, 2020, and the EU and the UK have concluded a trade and cooperation agreement, or TCA, which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities

for medicinal products and GMP documents issued but does not provide for wholesale mutual recognition of UK and EU pharmaceutical regulations.

At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the EU regulatory framework currently continues to apply in Northern Ireland).

The regulatory regime in Great Britain therefore largely aligns with current EU regulations, however it is possible that these regimes will diverge in the future now that Great Britain’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of UK and EU pharmaceutical legislation.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued but does not provide for wholesale mutual recognition of UK and EU pharmaceutical regulations.

At present, the UK has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended).

The regulatory regime in the UK therefore largely aligns with current EU regulations, however it is possible that these regimes will diverge in the future now that the UK’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of UK and EU pharmaceutical legislation.

For example, the EU Clinical Trials Regulation does not apply in the UK and the current UK clinical trials legislation is based on the now repealed Clinical Trials Directive 2001/20/EC.

However, the MHRA published details of its legislative proposals designed to improve and strengthen the UK clinical trials legislation on March 21, 2023.

The legislative proposals were published in response to a consultation which ran from January 17, 2022 to March 14, 2022.

The MHRA will now work with lawyers to draft such new legislation.

Notwithstanding that there is no wholesale recognition of EU pharmaceutical legislation under the TCA, under a new framework mentioned above which was put in place by the MHRA on January 1, 2024, the MHRA may take into account decisions on the approval of marketing authorizations from the EMA (and certain other regulators) when considering an application for a Great Britain marketing authorizations.

However, on December 12, 2024, the UK government introduced a legislative proposal – the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2024 – that, if implemented, will replace the current regulatory framework for clinical trials in the UK.

The legislative proposal aims to provide a more flexible regime to make it easier to conduct clinical trials in the UK and increase the transparency of clinical trials conducted in the UK.

This includes a notification scheme to enable lower-risk clinical trials to be automatically approved by the MHRA, where the risk is similar to that of standard medical care (although such trials would still require ethics committee approval).

Such Regulations are expected to come into force in early 2026.

Notwithstanding that there is no wholesale recognition of EU pharmaceutical legislation under the TCA, under a new framework put in place by the MHRA on January 1, 2024, the MHRA may take into account decisions on the approval of marketing authorizations from the EMA (and certain other regulators) when considering an application for UK marketing authorizations.

On February 27, 2023, the UK government and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”.

The Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, and the medicines aspects of the Windsor Framework have applied since January 1, 2025.

This new framework fundamentally changes the existing system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the UK.

In particular, the MHRA will be responsible for approving all medicinal products destined for the UK market (Great Britain and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland.

A single UK-wide marketing authorization will be granted by the MHRA for all medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.

The Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, so the UK government and the EU will enact legislative measures to bring it into law.

On June 9, 2023, the MHRA announced that the medicines aspects of the Windsor Framework will apply from January 1, 2025.

In particular, the MHRA is now responsible for approving all medicinal products destined for the UK market (Great Britain and Northern Ireland), and the EMA no longer has any role in approving medicinal products destined for Northern Ireland under the EU centralized procedure.

A single UK-wide marketing authorization will be granted by the MHRA for all novel medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.

In addition, the new arrangements require all medicines placed on the UK market to be labeled “UK only”, indicating they are not for sale in the EU.

The Foreign Corrupt Practices Act

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Human Capital

As of March 1, 2024, we had 154 full-time employees and 0 part-time employees, 39 of whom have Ph.D.

As of February 28, 2025, we had 194 full-time employees and 1 part-time employee, 41 of whom have Ph.D.

Of these full-time employees, 158 employees are engaged in research and development activities and 36 are engaged in finance, business development and other general and administrative functions.

13 unchanged sentences

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 October 2029.

The facility at 830 Winter Street is 51,100 square feet consisting of GMP clean room, laboratory, warehouse and office space, with a lease expiration of October 2029.

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.

16 unchanged sentences

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