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Item 1. Business

2024-03-14 compared with 2023-02-28 · 411 added, 481 removed, 559 unchanged (61% of the section changed)

We are a clinical stage immuno-oncology company pioneering the development of genetically engineered allogeneic T cell product candidates for the treatment of cancer.

We are developing a pipeline of off-the-shelf T cell product candidates that are designed to target and kill cancer cells.

We are a clinical stage immuno-oncology company pioneering the development of genetically engineered allogeneic T cell product candidates for the treatment of cancer and autoimmune diseases.

We are developing a pipeline of “off-the-shelf” T cell product candidates that are designed to target and kill cancer cells in patients or eliminate pathogenic autoreactive cells in patients with autoimmune disorders.

Our engineered T cells are allogeneic, meaning they are derived from healthy donors for intended use in any patient, rather than from an individual patient for that patient’s use, as in the case of autologous T cells.

We believe this key difference will enable us to deliver readily available treatments faster, more reliably, at greater scale, and to more patients.

Chimeric antigen receptor (CAR) T cell therapy, a form of cancer immunotherapy, has emerged as a revolutionary and potentially curative therapy for patients with hematologic cancers, including refractory cancers.

In 2017, the first two autologous anti-CD19 CAR T cell therapies, Kymriah, developed by Novartis International AG (Novartis), and Yescarta, developed by Kite Pharma, Inc.

(Kite), were approved by the U.S.

Food and Drug Administration (FDA) for the treatment of relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) (Kymriah) and R/R large B-cell lymphoma (Yescarta).

Autologous CAR T cell therapies are manufactured individually for the patient’s use by modifying the patient’s own T cells outside the body, causing the T cells to express CARs.

The entire manufacturing process is dependent on the viability of each patient’s T cells and takes approximately two to four weeks.

Obtaining a manufacturing slot, collecting patient cells, and scheduling can extend the time to treatment by additional weeks.

As seen in the registrational trials for Kymriah and Yescarta, up to 31% of intended patients ultimately did not receive treatment primarily due to interval complications from the underlying disease prior to delivery of therapy or manufacturing failures.

Earlier this year, we announced our 2024 Platform Vision that we believe will redefine the future of chimeric antigen receptor (CAR) T therapy by leveraging the unique attributes of allogeneic CAR T products.

Under our 2024 Platform Vision we are focusing on four core programs:

Large B-Cell Lymphoma (LBCL) :

Potentially groundbreaking ALPHA3 Trial that we believe may leapfrog other CAR T’s and embed cemacabtagene ansegedleucel (cema-cel, previously ALLO-501A) in first line (1L) LBCL treatment in community cancer centers where most newly diagnosed patients seek care.

Chronic Lymphocytic Leukemia (CLL) :

New Phase 1 ALPHA2 Cohort is designed to evaluate cema-cel as a CLL treatment in order to address the limitations of autologous therapies in a disease where poor T cell fitness is a known barrier to efficacy.

Autoimmune Disease (AID) :

ALLO-329, our next-generation CD19 Dagger® program, focuses on scalability and reduced or chemotherapy-free lymphodepletion, positioning allogeneic CAR T to potentially transform autoimmune management and meet the demand of the market.

Renal Cell Carcinoma (RCC) :

Ongoing TRAVERSE trial with ALLO-316 seeks to advance scientific innovation underlying the Dagger® technology to optimize CAR T cell expansion and persistence, thereby maximizing the potential of allogeneic CAR T in solid tumors while mitigating treatment-associated inflammatory response.

Our allogeneic approach involves engineering healthy donor T cells, which we believe will allow for the creation of an inventory of off-the-shelf products that can be delivered to a larger portion of eligible patients throughout the world.

These potential benefits led our Executive Chair, Arie Belldegrun, M.D., FACS, who was previously the Chair and Chief Executive Officer at Kite, and our President and Chief Executive Officer, David Chang, M.D., Ph.D., previously Chief Medical Officer and Executive Vice President of Research and Development at Kite, to found our company with the driving purpose of accelerating the development of allogeneic CAR T cell therapies.

We have multiple clinical trials ongoing and have a deep pipeline to further the research and development of allogeneic CAR T cell product candidates in both hematological malignancies and solid tumors.

We believe our technology platform combined with our management team’s experience in immuno-oncology and specifically in CAR T cell therapy will help drive the rapid development and, if approved, the commercialization of potentially curative therapies for patients with aggressive cancer.

Our allogeneic T cell development strategy has four key pillars:

(1) engineering product candidates to minimize the risk of graft-versus-host disease (GvHD), a condition where allogeneic T cells can recognize the patient’s normal tissue as foreign and cause damage, (2) creating a window of persistence that may enable allogeneic T cells to expand and eradicate cancer cells in patients, (3) building a leading manufacturing platform to enable consistent and high quality production and (4) leveraging next generation technologies to improve the functionality of allogeneic CAR T cells.

We use Cellectis, S.A.

(Cellectis), TALEN gene-editing technology to limit the risk of GvHD by engineering T cells to lack functional T cell receptors (TCRs) that are no longer capable of recognizing a patient’s normal tissue as foreign.

With the goal of enhancing the expansion and persistence of our engineered allogeneic T cells, we use TALEN to inactivate the CD52 gene in donor T cells and an anti-CD52 monoclonal antibody to deplete CD52 expressing T cells in patients while sparing the therapeutic allogeneic T cells.

These potential benefits led our Executive Chair, Arie Belldegrun, M.D., FACS, who was previously the Chair and Chief Executive Officer at Kite Pharma (Kite, now a Gilead company), and our President and Chief Executive Officer, David Chang, M.D., Ph.D., previously Chief Medical Officer and Executive Vice President of Research and Development at Kite, to found our company with the driving purpose of accelerating the development of allogeneic CAR T cell therapies.

Although we are currently focusing on our four core development programs noted above, we continue to have a deep pipeline to further the research and development of allogeneic CAR T cell product candidates in both hematological malignancies and solid tumors.

Our allogeneic CAR T cell development strategy has four key pillars:

(1) engineering product candidates to minimize the risk of graft-versus-host disease (GvHD), a condition where allogeneic T cells can recognize the patient’s normal tissue as foreign and cause damage, (2) creating a window of persistence that may enable allogeneic T cells to expand and eradicate cancer cells in patients or pathogenic autoreactive cells in patients, (3) building a leading manufacturing platform to enable consistent and high quality production and (4) leveraging next generation technologies to improve the functionality of allogeneic CAR T cells.

For our oncology programs we use Cellectis, S.A.

(Cellectis), TALEN® gene-editing technology to limit the risk of GvHD by engineering T cells to lack functional T cell receptors (TCRs), thereby preventing them from recognizing a patient’s normal tissue as foreign.

With the goal of enhancing the expansion and persistence of our engineered allogeneic T cells, we use

TALEN® technology to inactivate the CD52 gene in donor T cells and an anti-CD52 monoclonal antibody to deplete CD52 expressing T cells in patients while sparing the therapeutic allogeneic T cells.

We believe this enables a window of persistence for the infused allogeneic T cells to actively target and destroy cancer cells.

We are also developing ALLO-647, our own anti-CD52 monoclonal antibody, which is

designed to be used prior to infusing our other product candidates as part of a lymphodepletion regimen.

Our off-the-shelf approach is dependent on state-of-the-art manufacturing processes, and we are continuing to build a technical operations organization with fully integrated in-house expertise in clinical and commercial engineered T cell manufacturing.

We are also developing ALLO-647, our own anti-CD52 monoclonal antibody, which is designed to be used prior to infusing our other product candidates as part of a lymphodepletion regimen.

Our off-the-shelf approach is dependent on state-of-the-art manufacturing processes, and we believe we have built a technical operations organization with fully integrated in-house expertise in clinical and commercial engineered T cell manufacturing.

For our lead autoimmune program, we have a non-exclusive license with Arbor Biotechnologies relating to a CRISPR-based gene-editing technology for the development of allogeneic T cell product candidates directed against various targets, including CD19 and CD70 both of which ALLO-329 targets.

We have built our own current good manufacturing practices (cGMP) manufacturing facility in Newark, California, that we call Cell Forge 1 (CF1).

We are currently assessing the product candidates for manufacturing at CF1.

Finally, we plan to leverage next generation technologies, such as to develop more potent product candidates and to develop product candidates to overcome premature rejection of allogeneic CAR T cells by the patient immune system.

We believe next generation technologies will also allow us to develop allogeneic T cell therapies for the treatment of solid tumors, which to date have been difficult to treat because of the lack of validated targets and tumor microenvironments that can impair the activity of T cells.

We are currently utilizing CF1 for clinical manufacturing of our product candidates.

Finally, we plan to leverage next generation technologies to develop more potent product candidates and to develop product candidates to overcome premature rejection of allogeneic CAR T cells by the patient’s immune system.

We believe next generation technologies will also allow us to further develop allogeneic T cell therapies for the treatment of solid tumors, which to date have been difficult to treat because of, among other factors, the lack of validated targets and tumor microenvironments that can impair the activity of T cells.

We are currently developing a pipeline of multiple allogeneic CAR T cell product candidates utilizing protein engineering, gene editing, gene insertion and advanced proprietary T cell manufacturing technologies.

Our most advanced product candidates, ALLO-501 and ALLO-501A, are engineered allogeneic CAR T cell product candidates that target CD19, a protein expressed on the cell surface of B cells and a validated target for B cell driven hematological malignancies.

We are also developing engineered allogeneic CAR T cell product candidates for multiple myeloma, clear cell renal cell carcinoma (ccRCC), and other blood cancers and solid tumors.

Our most advanced product candidate, cemacabtagene ansegedleucel, referred to as cema-cel (previously ALLO-501A), is an engineered allogeneic CAR T cell product candidate that targets CD19, a protein expressed on the cell surface of B cells and a validated target for B cell driven hematological malignancies.

We are currently focused on developing cema-cel for LBCL and CLL.

Our pipeline also includes ALLO-316 and ALLO-329.

ALLO-316 is an engineered allogeneic CAR T cell product candidate that targets CD70, which is highly expressed in RCC and is selectively expressed in several other cancers thereby creating the potential for ALLO-316 to be developed across a variety of both hematologic malignancies and solid tumors.

We are currently focused on developing ALLO-316 for RCC.

ALLO-329, an engineered allogeneic CAR T cell product candidate that targets both CD19 and CD70, is in development for the treatment of certain AIDs.

We also have additional product candidates, but we have deprioritized these programs to allow us to focus on cema-cel, ALLO-316 and ALLO-329.

Our pipeline is represented in the diagram below.

1 Phase 3 may not be required if Phase 2 is registrational

2 ALLO-647 is intended to enable expansion and persistence of allogeneic CAR T product candidates;

2 ALLO-647 (anti-CD52 mAb) is intended to enable expansion and persistence of allogeneic CAR T product candidates

Our lead product candidates include:

We are sponsoring a Phase 1 clinical trial (the ALPHA trial) of ALLO-501 in patients with the most common R/R non-Hodgkin lymphoma (NHL) subtypes, including R/R large B-cell lymphoma (LBCL) and R/R follicular lymphoma (FL).

We completed accrual in the ALPHA trial in 2021 and are following patients as part of long-term follow-up.

We have removed rituximab recognition domains in our second-generation version of ALLO-501, known as ALLO-501A, which we believe will potentially facilitate treatment of more patients, as rituximab is a typical part of a treatment regimen for a patient with NHL.

We initiated a Phase 1/2 clinical trial for ALLO-501A (the ALPHA2 trial) in the second quarter of 2020.

The Phase 1 portion of the ALPHA2 trial was designed to assess the safety and tolerability at increasing dose levels of ALLO-501A in patients with R/R LBCL or transformed FL.

Updated results from the ALPHA trial and ALPHA2 trial were presented at our November 2022 R&D Showcase.

See “—Product

Pipeline and Development Strategy—Anti-CD19 Development Program—Results from the Phase 1 ALLO-501 ALPHA Trial and the Phase 1 ALLO-501A ALPHA2 Trial” for information regarding the results.

In the fourth quarter of 2022, we proceeded to the Phase 2 portion of the ALPHA2 trial in adult patients with R/R LBCL.

We expect to complete enrollment of the Phase 2 portion of the ALPHA2 trial in the first half of 2024.

Subject to further patient follow-up and FDA discussion, we plan to initiate a Phase 3 clinical trial of ALLO-501A in an earlier line of therapy for LBCL in the first half of 2024.

We are sponsoring a Phase 1 clinical trial (the UNIVERSAL trial) of ALLO-715, an allogeneic CAR T cell product candidate targeting B-cell maturation antigen (BCMA), in adult patients with R/R multiple myeloma.

We presented updated results from the UNIVERSAL trial at our R&D Showcase in November 2022 as well as at the American Society of Hematology annual meeting in December 2022.

See “—Product Pipeline and Development Strategy—Anti-BCMA Development Program—Results from the Phase 1 ALLO-715 UNIVERSAL Trial” for information regarding the results.

We are sponsoring a Phase 1 clinical trial (the IGNITE trial) of ALLO-605, an allogeneic CAR T cell product candidate targeting BCMA, in adult patients with R/R multiple myeloma.

ALLO-605 is our first product candidate to incorporate our TurboCAR technology.

TurboCAR technology allows cytokine signaling to be engineered selectively into CAR T cells and has shown the ability to improve the potency and persistence of the cells and to delay exhaustion of the cells in preclinical models.

We are currently reviewing and optimizing the manufacturing process for our BCMA program and are not enrolling patients in the UNIVERSAL and IGNITE trials at this time.

We are sponsoring a Phase 1 clinical trial (the TRAVERSE trial) of ALLO-316, an allogeneic CAR T cell product candidate targeting CD70, in adult patients with advanced or metastatic ccRCC.

We presented preliminary results from the TRAVERSE trial at our November 2022 R&D Showcase.

• Cemacabtagene ansegedleucel (cema-cel).

We are currently focused on developing cema-cel in LBCL and CLL.

We plan to initiate a pivotal Phase 2 clinical trial (ALPHA3) in mid-2024 for cema-cel as part of a 1L treatment plan for newly diagnosed and treated LBCL patients who are likely to relapse and need further therapy.

(Foresight Diagnostics) that we believe will identify patients who have achieved remission by standard disease assessment but who have minimal residual disease (MRD) at the completion of 1L chemoimmunotherapy.

The ALPHA3 trial is designed to study the impact of treating MRD positive patients with cema-cel.

The study will randomize approximately 230 patients who achieve a complete response or partial response to 1L therapy, but who are MRD positive.

The patients will be randomized to either consolidation with cema-cel or the current standard of care, which is observation.

The design, with a primary endpoint of event free survival (EFS), will initially include two lymphodepletion arms (one with standard fludarabine and cyclophosphamide plus ALLO-647 and one with standard fludarabine and cyclophosphamide but without ALLO-647).

One lymphodepletion arm will be discontinued following a planned interim analysis in mid-2025 designed to select the most appropriate regimen for this patient population.

In view of the potential of the earlier line ALPHA3 trial, we have deprioritized the third line (3L) LBCL ALPHA2 and EXPAND trials.

We have initiated the Phase 1b cohort of our ALPHA2 trial to evaluate cema-cel following lymphodepletion with fludarabine/cyclophosphamide and ALLO-647 in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

This cohort will include up to 40 patients, and we expect to release initial data by year-end 2024.

We are enrolling a Phase 1 clinical trial (TRAVERSE) of ALLO-316, an allogeneic CAR T cell product candidate targeting CD70, in adult patients with advanced or metastatic RCC.

We presented interim results from the TRAVERSE trial at the American Association of Cancer Research (AACR) Annual Meeting in April 2023.

See “—Product Pipeline and Development Strategy—Anti-CD70 Development Program—Results from the Phase 1 ALLO-316 TRAVERSE Trial” for information regarding the results.

Subject to ongoing results in the TRAVERSE trial, we intend to complete planned dose exploration and initiate expansion cohort enrollment in 2023.

We may also investigate the use of ALLO-316 for other CD70 expressing solid tumors and hematologic indications or in combination with other anticancer therapies such as immune checkpoint inhibitors.

We are developing an anti-CD52 monoclonal antibody, ALLO-647, which is a component of our lymphodepletion regimen.

We have implemented a protocol amendment that incorporates a diagnostic and treatment algorithm into the study design.

The algorithm is designed to mitigate the treatment-associated hyperinflammatory response without compromising the CAR T function needed to eradicate solid tumors.

The next update from this trial is planned for a publication in the second quarter of 2024 and will discuss the algorithm.

A more comprehensive data update from the ongoing trial with the updated protocol is planned for year-end 2024.

We are developing ALLO-329, a next-generation allogeneic CAR T cell product candidate targeting both CD19 and CD70 for the treatment of certain autoimmune diseases.

Inclusion of an anti-CD70 CAR in ALLO-329 incorporates the Dagger® technology, which is designed to reduce or eliminate the need for standard chemotherapy by preventing premature rejection while targeting CD19+ B-cells and CD70+ activated T-cells, both of which play a role in AID.

Initiation of this Phase 1 trial with ALLO-329 is expected in early 2025.

We are developing an anti-CD52 monoclonal antibody, ALLO-647, which is a proprietary component of our lymphodepletion regimen.

ALLO-647 may be able to reduce the likelihood of a patient’s immune system rejecting the engineered allogeneic T cells for a sufficient period of time to enable a window of persistence during which our engineered allogeneic T cells can actively target and destroy cancer cells.

We are currently assessing ALLO-647 in all of our clinical trials and are in the process of initiating a separate Phase 2 trial (the EXPAND trial) to assess ALLO-647 and its contribution to the overall benefit to risk ratio of the lymphodepletion regimen for ALLO-501A.

We expect the EXPAND trial to open to enrollment early in the second quarter of 2023.

As a part of this potentially registrational trial, patients will be randomized to receive the same single dose of ALLO-501A as in the ALPHA2 trial and either lymphodepletion with fludarabine and cyclophosphamide (control arm) or the lymphodepletion regimen of the ALPHA2 trial, inclusive of ALLO-647 (active arm).

During Part A of our pivotal ALPHA3 trial, we will be assessing ALLO-647’s contribution to the overall benefit to risk ratio of the lymphodepletion regimen for cema-cel.

Patients will be randomized to receive cema-cel and a lymphodepletion regimen with fludarabine and cyclophosphamide either with or without ALLO-647.

We plan to select the lymphodepletion regimen in mid 2025.

• Other Product Candidates:

While we have additional programs in our pipeline, our development priorities are focused on cema-cel (1L Consolidation and CLL), ALLO-316, and ALLO-329.

We will explore opportunities to partner with collaborators on product candidates across our pipeline.

Our History and Team

We believe we have established a leadership position in allogeneic T cell therapy.

We believe we have established a leadership position in allogeneic CAR T cell therapy.

In April 2018, we acquired certain assets from Pfizer Inc.

(Pfizer), including strategic license and collaboration agreements and other intellectual property related to the development and administration of allogeneic CAR T cells for the treatment of cancer.

We have an Exclusive License and Collaboration Agreement with Servier (the Servier Agreement) to develop and commercialize ALLO-501 and ALLO-501A, and we hold the commercial rights to these product candidates in the United States.

We also have an exclusive worldwide license from Cellectis to its TALEN gene-editing technology for the development of allogeneic T cell product candidates directed against 15 different cancer antigens.

The Servier Agreement gives us access to TALEN gene-editing technology for ALLO-501 and ALLO-501A.

We have an Exclusive License and Collaboration Agreement (the Servier Agreement) with Les Laboratoires Servier SAS and Institut de Recherches

Internationales Servier SAS (collectively, Servier) to develop and commercialize cema-cel, and we hold the commercial rights to these product candidates in the United States.

The Servier Agreement gives us access to Cellectis’ TALEN® gene-editing technology for cema-cel.

We also have an exclusive worldwide oncology license from Cellectis to use its TALEN® gene-editing technology for the development of allogeneic T cell product candidates directed against 15 different cancer antigens, including CD70 which ALLO-316 targets.

We also have a non-exclusive license with Arbor Biotechnologies relating to a CRISPR-based gene-editing technology for the development of allogeneic T cell product candidates in the field of autoimmune diseases directed against various targets, including CD19 and CD70 both of which ALLO-329 targets.

Our world-class management team has significant experience in immuno-oncology and in progressing products from early-stage research to clinical trials, and ultimately to regulatory approval and commercialization.

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Chang led the development and approval of Yescarta® at Kite.

Additionally, our Executive Vice President of Research and Development, Dr.

Zachary Roberts, was also instrumental in the development and execution of the clinical trials of Yescarta across multiple indications, and he most recently served as the Chief Medical Officer of Instil Bio, a cell therapy company, where he led development of both clinical and pre-clinical programs.

Our Chief Technical Officer, Alison Moore,

Ph.D., has over 25 years of experience in biotechnology and was previously Senior Vice President, Process Development at Amgen, where she led the development, deployment and oversight of manufacturing for approximately 80 multi-modality assets.

Our goal is to maintain and build upon our leadership position in allogeneic T cell therapy.

We plan to rapidly develop and, if approved, commercialize allogeneic T cell products for the treatment of cancer that can be delivered faster, more reliably and at greater scale than autologous T cell therapies.

We believe achieving this goal could result in allogeneic T cell therapy becoming a standard of care in cancer treatment and enable us to make potentially curative therapies more readily accessible to more patients throughout the world.

Additionally, our Executive Vice President of Research and Development and Chief Medical Officer, Dr.

Zachary Roberts, was also instrumental in the development and execution of the clinical trials of Yescarta® across multiple indications.

Our Chief Technical Officer, Timothy Moore, has over 30 years of leadership experience in biopharmaceutical manufacturing and operations and was previously Executive Vice President, Technical Operations at Kite, where he was responsible for the process development, manufacturing, quality and supply chain for Yescarta ® .

Our goal is to maintain and build upon our leadership position in allogeneic CAR T cell therapy.

We plan to rapidly develop and, if approved, commercialize allogeneic CAR T cell products for the treatment of cancer and autoimmune disease that can be delivered faster, more reliably, and at greater scale than autologous T cell therapies.

We believe achieving this goal could result in allogeneic CAR T therapy becoming a standard of care in cancer and autoimmune disease treatments and enable us to make potentially curative products more readily accessible to more patients throughout the world.

Key elements of our strategy include:

• Capitalize on a validated target and our leadership in engineered allogeneic anti-CD19 CAR T cell product candidates.

Autologous anti-CD19 CAR T cell therapies, such as Kymriah and Yescarta, have emerged as potentially curative therapies for B-cell lymphomas and leukemias.

We believe developing allogeneic CAR T cell product candidates targeting CD19 is the next frontier in delivering potentially curative therapies against B-cell lymphomas and leukemias.

We are focused on advancing ALLO-501A with the goal to complete enrollment in our Phase 2 ALPHA2 trial for R/R LBCL in the first half of 2024.

We also plan to initiate a Phase 3 trial of ALLO-501A in an earlier line of therapy for LBCL in the first half of 2024.

• Expand our leadership position within hematologic indications .

In addition to ALLO-501A, we plan to advance our near-term pipeline against additional hematologic targets where there remains a high unmet need.

For example, we believe BCMA is a promising target, as initial results from the UNIVERSAL trial have shown encouraging efficacy and manageable safety.

We also plan to develop additional allogeneic T cell product candidates targeting other antigens found on hematologic malignancies, including ALLO-316 targeting CD70, which may be applicable to multiple hematological malignancies, and ALLO-819 targeting FLT3 for the treatment of AML.

• Repositioning our allogeneic CAR T product as the only CAR T to be part of a first line (1L) consolidation approach.

As described in our 2024 Platform Vision, we seek to redefine the future of CAR T by potentially repositioning our allogeneic CAR T product as the only CAR T to be part of a first line (1L) treatment plan for newly diagnosed and treated LBCL patients who are likely to relapse and need further therapy.

The design of the ALPHA3 1L consolidation trial builds upon the results demonstrated in the Phase 1 ALPHA2 trial and leverages an investigational diagnostic test developed by Foresight Diagnostics to identify patients who have MRD at the completion of 1L chemoimmunotherapy for treatment with cema-cel.

Start-up activities for the ALPHA3 trial are underway and the trial is expected to begin enrolling in mid-2024.

• Build state-of-the-art gene engineering and cell manufacturing capabilities .

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We believe a critical component to our success will be to leverage and expand our proprietary manufacturing know-how, expertise and capacity.

For instance, for our lead product candidate, ALLO-501A, we were able to identify and select a manufacturing process that was associated with robust clinical performance in Phase 1.

We call this process Alloy and are using the Alloy process to manufacture ALLO-501A for the ALPHA2 and EXPAND trials.

We plan to continue to optimize manufacturing for our other product candidates and plan to manufacture product at CF1, our state-of-the-art cell therapy manufacturing facility in Newark, California.

We believe establishing our own fully integrated manufacturing operations and infrastructure will allow us to continuously improve the manufacturing process, limit our reliance on contract manufacturing organizations (CMOs) and more rapidly advance the commercialization of any of our product candidates that receive regulatory approval.

For instance, for our lead product candidate, cema-cel, we were able to identify and select a manufacturing process that was associated with robust clinical performance in Phase 1.

We believe establishing our own fully integrated manufacturing operations and infrastructure will allow us to continuously improve the manufacturing process, limit our reliance on contract development and manufacturing organizations (CDMOs) and more rapidly advance the commercialization of any of our product candidates that receive regulatory approval.

• Expand into solid tumor indications with high unmet need and leverage next generation technologies to advance our platform.

We plan to continue to advance the research and development of product candidates directed against a broad portfolio of solid tumor targets, including CD70 for the treatment of ccRCC, DLL3 for the treatment of small cell lung cancer and other aggressive neuroendocrine tumors, and Claudin 18.2 for the treatment of gastric and pancreatic cancer.

We also plan to leverage next generation technologies to make more potent allogeneic CAR T cells and improve the characteristics of our product candidates.

In addition, we are investigating next-generation technologies to control rejection of allogeneic CAR T cells by the patient immune system, such as with our Dagger technology that utilizes an anti-CD70 CAR to kill alloreactive host T cells.

We plan to continue to advance the research and development of ALLO-316, which targets CD70, for the treatment of clear cell renal cell carcinoma (ccRCC) as part of our TRAVERSE trial.

We are investigating next-generation technologies incorporated in the design of ALLO-316 which seek to better control rejection of allogeneic CAR T cells by the patient immune system.

Such technologies include our Dagger® technology that utilizes an anti-CD70 CAR to kill alloreactive host T cells.

We are also advancing technologies to increase specificity of CAR T activity to avoid potential normal tissue toxicities associated with certain solid tumor targets.

We continually survey the scientific and industry landscape for opportunities to license, partner or acquire technologies that may help us advance current or new cell therapies for the benefit of patients.

• Accelerate the development of our product candidates across geographies .

We are positioning ourselves to pursue clinical development of product candidates in additional markets around the world.

Subject to our clinical progress in the United States, we plan to initiate clinical trials in Europe, Canada and Australia, among other geographies.

In addition, in December 2020, we jointly formed Allogene Overland Biopharm (CY) Limited for the development, manufacturing and commercialization of certain of our product candidates targeting BCMA, CD70, FLT3, and DLL3 in China, Taiwan, South Korea and Singapore.

Allogene Overland has completed the buildout of a cell manufacturing facility in China and is beginning to progress product manufacturing ahead of clinical trial evaluation.

We may selectively partner with other third parties to develop and commercialize our product candidates in additional countries.

Allogeneic T Cell Therapy

The Immune System and Cancer

White blood cells are a component of the immune system and are responsible for defending the body against infectious pathogens and other foreign material.

T cells are a type of white blood cell and are involved in both sensing and killing infected or abnormal cells, including cancer cells, as well as coordinating the activation of other cells in an immune response.

T cells can be distinguished from other white blood cells by T cell receptors present on their cell surface.

These receptors contribute to tumor surveillance by directing T cells to recognize and destroy cancerous cells.

When T cells with cancer-specific receptors are absent, present in low numbers, of poor quality or rendered inactive by suppressive mechanisms, cancer may grow and spread.

In addition, standard of care treatments, such as chemotherapy regimens, as well as disease specific factors can damage the patient’s immune system, thereby inhibiting the ability of T cells to kill cancer.

• Expand our allogeneic CAR T platform into the treatment of autoimmune disease (AID).

We are currently developing a next-generation product candidate, ALLO-329, which will be an engineered allogeneic CAR T cell product candidate that targets CD19 and CD70.

ALLO-329 will incorporate our Dagger® technology.

We are currently focused on developing ALLO-329 for AID.

Incorporation of the Dagger® technology into an “off-the-shelf” CD19 product for use in AID is designed to reduce or eliminate the need for standard chemotherapy while targeting CD19+ B-cells and CD70+ activated T-cells, both of which play a role in AID.

Initiation of this Phase 1 trial with ALLO-329 is expected in early 2025.

Allogeneic CAR T Cell Therapy

Engineered T Cell Therapies

Engineered T cell therapy is a type of immunotherapy treatment whereby human T cells are removed from the body and engineered to express CARs which, when infused into a patient, may allow the recognition and destruction of cancer cells in a targeted manner.

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CARs are engineered molecules that, when present on the surface of a T cell, enable the T cell to recognize specific proteins or antigens that are present on the surface of other cells.

The CAR in our product candidates is comprised of a single chain protein that contains the following elements:

More than one type of CAR can be included in a CAR T cell, imparting multi-antigen targeting capability.

The CAR molecule(s) in our product candidates are comprised of a single chain protein that contains the following elements:

• Target Binding Domain:

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• Activating Domains:

The other end of transmembrane domain, inside the T cell, is connected to two contiguous domains responsible for activating the T cell when the CAR binds to the target cell.

The other end of transmembrane domain, inside the T cell, is connected to one or more signaling domains responsible for activating the T cell when the CAR binds to the target cell.

The CD3 zeta domain delivers an essential primary signal within the T cell, and the 41BB domain delivers an additional, co-stimulatory signal.

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In addition, activated CAR T cells stimulate the local secretion of cytokines and other molecules that can recruit and activate additional immune cells to potentiate killing of the cancer cells.

In addition to the domains described above, ALLO-715 possesses two rituximab-recognition domains between the scFv and the hinge which allow it to be recognized and eliminated by rituximab.

ALLO-501 possesses rituximab recognition domains in a separate polypeptide termed RQR8 that is co-expressed with the CAR.

We have removed rituximab recognition domains in ALLO-501A, which we believe will potentially facilitate treatment of more patients, as rituximab is a typical part of a treatment regimen for a patient with NHL.

In addition to the domains described above, in ALLO-316, we have included rituximab recognition domains to potentially serve as a way to identify and/or eliminate ALLO-316 cells using rituximab.

The figure below shows the constructs that support our lead product candidates in clinical development:

ALLO-501, ALLO-501A and ALLO-715.

Allogeneic T Cell Therapies:

cema-cel, ALLO-316 and ALLO-329.

Allogeneic CAR T Cell Products:

The Next Revolution

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autologous and allogeneic.

Autologous therapies use engineered T cells derived from the individual patient, while allogeneic therapies use engineered T cells derived from unrelated healthy donors.

The autologous approach, pioneered by Novartis and Kite, has been highly successful in engineering patients’ immune systems to fight cancer, in particular CD19 and BCMA expressing cancers, resulting in significant remission rates.

Autologous products are manufactured by first collecting a patient’s white blood cells, through a process known as leukapheresis, separating the T cells from the patient’s blood sample and proliferating the isolated T cells.

After the cells have multiplied, the CAR construct is virally transduced into the T cells and the engineered T cells are then propagated until a sufficient number of cells are available for infusion into the patient.

Finally, the engineered T cells are frozen, and then shipped back to the clinical center for administration to the patient.

The process from leukapheresis to delivery to the clinical center takes approximately two to four weeks.

Obtaining a manufacturing slot, collecting patient cells, and scheduling can extend the time to treatment by additional weeks.

Autologous therapies use engineered T cells derived from the individual patient, while allogeneic products use engineered T cells derived from unrelated

healthy donors.

While the autologous approach has been revolutionary, demonstrating compelling efficacy in many patients, it is burdened by the following key limitations:

• Lengthy Delivery Time .

Due to the individualized manufacturing process, patients may wait multiple weeks to be treated with their engineered cells.

As a result, in the registrational trials for Yescarta and Kymriah, up to 31% of intended patients ultimately did not receive treatment primarily due to interval complications from the underlying disease prior to delivery of therapy or manufacturing failures.

In addition, certain patients being treated with autologous product candidates have required bridging therapy as they wait for the manufacture of their T cells.

Bridging therapy to control disease may increase some cumulative or synergistic toxicities for the patients.

Due to the individualized manufacturing process, patients may wait weeks to months be treated with their engineered cells.

As a result, in the registrational trials for Yescarta® and Kymriah ® , up to 31% of intended patients ultimately did not receive treatment primarily due to complications from the underlying disease prior to delivery of therapy or as a result of manufacturing failures.

In addition, certain patients being treated with autologous therapies have sometimes required bridging therapy as they wait for the manufacture of their T cells, however, bridging therapy to control disease may increase some cumulative or synergistic toxicities for the patients.

Other rapidly progressing patients may not be considered candidates for autologous CAR T given lengthy waiting times and limited manufacturing slots.

Each of these autologous CAR T challenges creates inherent limitations to the uptake of autologous CAR T therapies.

As discussed in more detail below, these limitations become increasingly prohibitive in diseases where time is of the essence as is the case in 1L consolidation, making autologous CAR T therapy unsuitable for such use.

• Variable Potency .

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Furthermore, retreatment can be difficult due to a limited supply of usable patient starting material.

• High Production Cost .

• Complex Logistics .

The delivery of autologous T cell therapy is complicated due to the individualized nature of manufacturing, which allows only one patient to be treated from each manufacturing run and requires dedicated infrastructure to maintain a strict chain of custody and chain of identity of patient-by-patient material collection, manufacturing and delivery.

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• Availability and Access .

Starting with T cells from a healthy donor, we believe that at scale we can manufacture approximately 100 doses of allogeneic product that could be used in any eligible patient.

Because our allogeneic product candidates are designed to be frozen and available off-the-shelf, they could potentially be readily shipped and administered to patients.

We believe having an inventory of off-the-shelf allogeneic T cell products can also facilitate delivering multiple product doses to a patient over time.

Starting with T cells from a healthy donor, we believe that at scale we can manufacture approximately 100 doses or more of allogeneic CAR T product per manufacturing run that could be used in any eligible patient.

Because our allogeneic product candidates are designed to be frozen and available off-the-shelf, they are expected to be readily shipped and administered to patients.

• Speed to Patient .

Many patients with aggressive cancer or rapidly progressing cancer that is refractory to existing therapies may not have multiple weeks to wait for autologous T cell treatment.

Many patients with aggressive or rapidly progressing cancer may not have multiple weeks to wait for autologous CAR T treatment.

Our allogeneic approach has the potential to create off-the-shelf product inventory, which could enable dosing of patients within days of a decision to treat.

This would represent a significant reduction in patient wait time, potentially obviating the need for any bridging therapy and allowing the treatment of patients who are too sick to wait for the autologous therapy, and could improve patient outcomes.

This would represent a significant reduction in patient wait time, potentially obviating the need for any bridging therapy and allowing the treatment of patients who are either too sick, or their disease progresses to quickly for them to wait for their autologous CAR T cells to be manufactured, thus potentially improving patient outcomes.

In addition, as we seek to incorporate our investigational allogeneic CAR T product into a 1L consolidation strategy, the speed to patient becomes even more important.

Once it is determined that a patient is MRD positive following standard 1L treatment, published results of front-line chemotherapy outcomes suggest that the patient is very likely to progress, and some patients may do so very quickly (i.e., within a matter of weeks after completing 1L therapy).

Furthermore, data suggests that patients who have low burden of disease when they receive CAR T cells tend to have better safety and efficacy outcomes, including lower rates of cytokine release syndrome (CRS) and more durable remissions.

As a result, we believe that autologous CAR T therapy is far less suitable for treating MRD positive patients as part of a 1L consolidation strategy given the lengthy lead time for the autologous individualized manufacturing process, which would not allow for rapid CAR T treatment before disease progression and while the disease burden remains low.

• Enhanced Cell Consistency and Potency .

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In addition, greater consistency of the product may yield more predictable treatment outcomes.

• Streamlined Manufacturing and Cost Efficiencies .

• Streamlined Manufacturing .

We are building an efficient and scalable manufacturing process and organization.

The allogeneic approach utilizes healthy donor T cells which we believe provides enhanced scalability, reduces costs of engineered T cell therapy and reduces costs to the healthcare system as our allogeneic approach does not require us to collect and track T cells from each individual patient.

The allogeneic CAR T approach utilizes healthy donor T cells which we believe provides enhanced scalability, and an off-the-shelf capability that can potentially reduce the costs to the overall healthcare system as it does not require bridging therapy, leukapheresis and complex logistics.

Manufacturing Allogeneic T Cells

There are similarities as well as key differences between the processes for allogeneic and autologous T cell manufacturing, as illustrated in the figure below.

There are similarities as well as key differences between the processes for allogeneic and autologous CAR T cell manufacturing, as illustrated in the figure below which depicts our manufacturing process for our oncology CAR-T product candidates.

The three primary steps to creating our engineered allogeneic CAR T cells are:

(1) collection and transduction, (2) gene editing, and (3) purification, formulation, and storage.

Collection and Transduction

The starting material for our allogeneic T cell products is white blood cells from a healthy donor, which are collected using a standard blood bank procedure known as leukapheresis.

The collected cells are then screened, tested, and shipped to a central processing facility, where the T cells are isolated and stored frozen, creating an inventory of starting healthy donor cells for manufacturing.

The manufacturing process starts by thawing frozen healthy donor T cells, which are then stimulated to proliferate and transduced with a viral vector to integrate the CAR sequence into the T cell genome.

We start with collecting white blood cells from a healthy donor, which are subsequently stimulated to proliferate and transduced with a viral vector to integrate the CAR sequence into the T cell genome.

The CAR sequence directs the expression of CAR proteins on the cell surface that allows the transduced T cells to recognize and bind to a target molecule that is present on cancer cells.

We can concurrently add additional genes to these cells that confer specific properties.

For example, we can add an off-switch by expressing proteins that can make T cells susceptible to certain drugs, such as anti-CD20 monoclonal antibodies, and enable us to deplete our engineered T cells if needed by administering such drugs to the patient.

We can also introduce cytokine activation signaling within a CAR T cell that is designed to enhance the proliferative potential, migratory behavior, and killing activity of cells.

We are investigating multiple constructs designed to mimic cytokine signaling selectively within CAR T cells, a technology platform that we call “TurboCARs”.

We are also exploring the use of genetic engineering to control immune rejection of allogeneic CAR T cells, such as with an anti-CD70 CAR, which we call Dagger, to recognize and destroy allo-reactive host immune cells that would otherwise be capable of rejecting the allogeneic CAR T cells.

Next, we use Cellectis’s electroporation and TALEN technologies for gene editing of T cells.

TALENs are a class of DNA cutting enzymes derived by fusing the DNA-cutting domain of a nuclease to the DNA-binding domains from transcription activator-like effectors (TALE).

The TALE DNA-binding domain can be tailored to specifically recognize a unique DNA sequence.

These fusion proteins serve as readily targetable “DNA scissors” for genome engineering applications that can enable targeted genome modifications.

Electroporation allows TALEN mRNA to enter into the cell, where it is translated into a nuclease that can cut DNA and inactivate specific target genes.

Inactivation of genes, such as TCRα and CD52, is intended to reduce the risk of GvHD and allow the allogeneic T cells to expand and persist in patients.

We believe the inactivation of other target genes can be incorporated into future product candidates, with the goal of enhancing T cell function, including increasing potency against solid tumors.

The figure below illustrates how we utilize Cellectis’s TALEN and electroporation technology to inactivate the genes coding for TCRα and CD52 in our allogeneic T cells for UCART19.

We believe the key benefits of TALEN technology are:

• Precision .

It is possible to design a TALEN that will cleave at any selected region in any gene, giving us the ability to achieve the desired genetic outcome with any gene.

• Specificity and Selectivity .

TALEN may be designed to limit its DNA cleavage to the desired sequence and to reduce the risk of cutting elsewhere in the genome.

This parameter is essential, especially for therapeutic applications, because unwanted genomic modifications potentially could lead to harmful effects for the patient.

In addition, gene editing requires only a transient presence of TALEN, thus preserving the integrity and functionality of the T cell’s genome.

• Efficiency .

A large percentage of cells treated by the nuclease bear the desired genomic modification after treatment is completed.

We believe the efficiency of TALEN editing helps to improve our manufacturing yields.

TCR α knockout:

Non-modified allogeneic T cells bear functional TCRs and, if injected into a patient, can potentially recognize the patient’s tissue as foreign and damage it.

This reaction, known as GvHD, is mediated by intact TCRs on allogeneic T cells.

To reduce the risk of GvHD, all of our product candidates undergo the inactivation of a gene coding for

TCRα, a key component of TCRs.

The engineered T cells lacking functional TCRs are no longer capable of recognizing peptide antigens presented on major histocompatibility complex proteins and thus incapable of attacking the patient’s normal tissue.

This could mitigate the risk of GvHD that can occur when allogeneic TCR-positive T cells are infused into patients who are unrelated to the healthy donor, as shown in the figure below.

CD52 knockout:

The patient’s immune system is expected to recognize allogeneic T cells as foreign and destroy or reject them.

To delay this rejection, we use anti-CD52 antibody to deplete lymphocytes, including T cells, in patients.

Anti-CD52 antibody recognizes CD52 protein expressed on many immune cells, including T cells.

CD52 protein is expressed in both donor and patient immune cells.

To selectively deplete a patient’s immune cells while sparing the therapeutic allogeneic T cells, we use TALEN gene editing to inactivate the CD52 gene in allogeneic T cells, thus protecting allogeneic T cells from the anti-CD52 antibody mediated depletion.

As illustrated below, by administering anti-CD52 antibody prior to infusing our product candidates, we believe we can reduce the likelihood of a patient’s immune system rejecting the engineered allogeneic T cells for a sufficient period of time to enable a window of persistence during which our engineered allogeneic T cells can expand and actively target and destroy cancer cells.

We also believe our approach is unique and differentiated.

To capitalize on this differentiation and to secure our own source of anti-CD52 monoclonal antibody, we are developing ALLO-647.

We are currently assessing ALLO-647 in all of our clinical trials and are in the process of initiating a potentially pivotal Phase 2 trial for ALLO-647 as part of the lymphodepletion regimen for ALLO-501A.

Purification, Formulation, and Storage

Once the allogeneic T cells have been engineered with CARs and gene edited to remove the genes encoding TCRα and CD52, they are cultured for several days to increase the cell number and then harvested.

The allogeneic cells then undergo a purification step to remove residual TCR positive cells that have not undergone TCRα gene editing.

We believe this purification step is essential as none of the currently available gene-editing nucleases is 100% efficient at inactivating the target genes.

After overnight recovery, the cells are formulated in a cryopreservation media and filled into closed, stoppered vials prior to controlled-rate freezing and long-term storage in the vapor phase of liquid nitrogen.

This inventory is securely stored and then shipped to oncology centers as needed.

The figure below illustrates the steps in a manufacturing run for our engineered allogeneic CAR T product candidates.

Next, we use gene editing tools to edit the T cell genome to inactivate TCRα and CD52.

Inactivation of TCRα and CD52 is intended to reduce the risk of GvHD and allow the allogeneic

T cells to expand and persist in patients, respectively.

Finally, the edited T cells are cultured for several days to increase the cell number, harvested and purified.

The purified T cells are formulated in a cryopreservation media and filled into closed, stoppered vials prior to controlled-rate freezing and long-term storage in the vapor phase of liquid nitrogen.

This inventory is securely stored and then shipped to treatment facilities, as needed.

The figure below illustrates the steps in a manufacturing run for our engineered oncology allogeneic CAR T product candidates.

Product Pipeline and Development Strategy

Using our proprietary allogeneic T cell platform, we are researching and developing multiple product candidates for the treatment of blood cancers and solid tumors.

Our product candidates are allogeneic T cells engineered to be used as off-the-shelf treatments for any patient with a particular cancer type.

Each product candidate targets a selected antigen expressed on tumor cells and bears specific engineered attributes.

Our product pipeline is represented in the diagram below:

Using our proprietary allogeneic CAR T cell platform, we are researching and developing multiple product candidates for the treatment of blood cancers, solid tumors and autoimmune diseases.

Our product candidates are allogeneic T cells engineered to be used as off-the-shelf treatments for any patient with a particular cancer type or autoimmune disease.

Each product candidate bears specific engineered attributes, and targets a selected antigen expressed on tumor cells or pathogenic autoreactive immune cells.

Our product pipeline is represented in the chart below:

1 Phase 3 may not be required if Phase 2 is registrational;

2 ALLO-647 is intended to enable expansion and persistence of allogeneic CAR T product candidates;

In October 2021, the FDA placed a hold on our clinical trials.

The clinical hold followed our notification to the FDA of a chromosomal abnormality in an ALPHA2 study patient which was detected in a bone marrow biopsy undertaken to assess pancytopenia.

Investigations concluded that the chromosomal abnormality was unrelated to TALEN gene editing or our manufacturing process and had no clinical significance.

The investigation also determined that the abnormality was not detected in any of our manufactured product candidates or in any other patient treated with the same ALLO-501A lot.

The abnormality occurred in the patient after the cell product was administered and involved regions of the T cell receptor and immunoglobulin genes known to undergo rearrangement as part of the T cell or B cell maturation process.

The FDA found that we satisfactorily addressed all clinical hold issues and removed the hold in January 2022.

We have resumed our studies as discussed in further detail below.

Anti-CD19 Development Program

Anti-CD19 Oncology Development Program

CD19 is an antigen expressed on the surface of B cells, including on B cells that are malignant.

B cells are considered non-essential tissue, as they are not required for patient survival.

B cells are considered non-essential tissue, as they are not absolutely required for patient survival.

We believe CD19 is a validated target for the treatment of B cell leukemias and lymphomas.

Multiple autologous anti-CD19 targeted CAR T therapies have shown promising results and have been approved by the FDA as therapies in multiple blood cancers, including R/R LBCL, as further described below under "—Competition".

Our first anti-CD19 product candidate, UCART19, was advanced with Servier, who led manufacturing and clinical development.

UCART19 was manufactured to express a CAR that is designed to target CD19 and gene edited to lack TCRα and CD52 to minimize the risk of GvHD and enable a window of persistence in the patient.

Multiple autologous anti-CD19 CAR T therapies have shown promising results and have been approved by the FDA as therapies in multiple blood cancers, including relapsed/refractory (R/R) LBCL, as further described below under "—Competition".

Historically, under our Servier Agreement, we have worked with Servier to develop several CD19 product candidates, including UCART19, ALLO-501 and cema-cel.

On September 15, 2022, Servier sent us a notice of discontinuation of its involvement in the development of all CD19 Products pursuant to the Servier Agreement.

While we continue to work to redefine our relationship with Servier, in the interim, we have assumed all responsibility for the CD19 development program.

UCART19 was our first CD19 product candidate, and Servier led its manufacturing and clinical development.

UCART19 was manufactured to express a CAR that is designed to target CD19 and gene edited to lack TCRαβ and CD52 to minimize the risk of GvHD and enable use of anti-CD52 monoclonal antibodies to create a window of CAR T cell persistence in the patient.

In addition, UCART19 cells were engineered to express a small protein on the cell surface called RQR8, which consists of two rituximab recognition domains.

This allowed for recognition and elimination of cells in the event that silencing of CAR T cell activity is desired.

Servier sponsored two Phase 1 clinical trials of UCART19 in patients with R/R CD19 positive B-cell ALL, one for adult patients (the CALM trial) and one for pediatric patients (the PALL trial).

The Servier-sponsored trials completed in 2020 and Servier determined that no new patients will be enrolled.

This allowed for recognition and elimination of the CAR T cells by rituximab in the event that silencing of CAR T cell activity is desired.

Servier sponsored two Phase 1 clinical trials of UCART19 in patients with R/R CD19 positive B-cell acute lymphoblastic leukemia (ALL), both of which were completed in 2020.

Patients from both studies are continuing the long-term follow-up as planned.

We are reviewing our development strategy for ALL as our data matures and as we assess potential next generation technology that may be used to enhance results in ALL.

ALLO-501 and ALLO-501A are our other allogeneic CAR T cell product candidates targeting CD19, which are also part of the Servier Agreement.

We are responsible for the manufacture of ALLO-501 and ALLO-501A.

We also lead the clinical development program and are sponsoring the ALPHA trial of ALLO-501 and ALPHA2 trial of ALLO-501A, each for patients with R/R NHL.

ALLO-501 is identical to UCART19 in molecular design, however several modifications have been introduced by us to the manufacturing process for ALLO-501.

We have been, and continue to be, responsible for the manufacture and clinical development of ALLO-501 and cema-cel.

ALLO-501 is identical to UCART19 in molecular design, however several modifications were introduced by us to the manufacturing process for ALLO-501.

These modifications are designed to facilitate more efficient manufacturing scale-up for the larger patient population targeted by ALLO-501.

Like UCART19, ALLO-501 also co-expresses a small protein on the cell surface called RQR8, which consists of two rituximab recognition domains.

This allows for destruction of the CAR T by rituximab.

Prior treatment with rituximab is typical for patients with NHL and, depending on the lag time between the rituximab administration and planned ALLO-501 infusion, prior administration of rituximab may interfere with ALLO-501.

As a result, we have removed RQR8 in the next generation of ALLO-501, known as ALLO-501A.

We believe ALLO-501A will have the potential to facilitate treatment of patients who were recently treated with rituximab.

This is intended to allow for destruction of the CAR T by rituximab.

Prior treatment with rituximab is typical for patients with Non-Hodgkin Lymphoma (NHL) and, depending on the lag time between the rituximab administration and the CAR T infusion, prior administration of rituximab may interfere with any CAR T that includes RQR8.

As a result, we have removed RQR8 in cema-cel, which is illustrated below, to facilitate treatment of patients who were recently treated with rituximab.

Lead Target Indication:

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B-cell NHL itself represents a group of different neoplasms that not only differ in pathology, but also response to therapy and prognosis.

NHL can be rapidly growing (aggressive), such as large B-cell lymphomas, which include diffuse large B cell lymphoma (DLBCL), or it can be slow growing, or indolent, such as FL.

The R-CHOP chemotherapy combination (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) introduced in the early 2000s remains the standard of care for newly diagnosed DLBCL, and can yield five-year survival rates of 55-60%.

Unfortunately, approximately 30% of DLBCL relapse and require second-line therapy.

NHL can be rapidly growing (aggressive), such as LBCLs, or it can be slow growing, or indolent, such as follicular lymphoma (FL).

The R-CHOP chemotherapy combination (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) introduced in the early 2000s remains the standard of care for newly diagnosed LBCL, and can yield five-year survival rates of 55-60%.

Unfortunately, approximately 30% of LBCL patients relapse or have treatment-refractory disease and require second-line therapy.

Subsequent therapy for fit patients is commonly high-dose therapy followed by autologous stem-cell therapy or autologous anti-CD19 CAR T therapy.

Two recent randomized controlled trials evaluated anti-CD19 CAR T cell therapies, Yescarta and Breyanzi, compared to high dose chemotherapy followed by autologous stem cell rescue.

Two previous randomized controlled trials evaluated anti-CD19 CAR T cell therapies, Yescarta® and Breyanzi® compared to high dose chemotherapy followed by autologous stem cell rescue.

Yescarta® and Breyanzi® improved event-free-survival versus stem cell transplant (8.3 months vs.

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2.3 months, respectively).

Overall survival from these randomized trials is pending;

however, a retrospective analysis of patients with R/R DLBCL, who were not treated with autologous CAR T therapy, found that outcomes in this population are poor, with an objective response rate of 26% (complete response (CR):

A retrospective analysis of patients with R/R LBCL, who were not treated with autologous CAR T therapy, found that outcomes in this population are poor, with an objective response rate of 26% (complete response (CR):

7%, partial response:

18%) and median overall survival of 6.3 months.

Despite availability of multiple active agents, high response rates, and long progression-free survival with first-line therapy, FL remains an incurable disease.

Most patients treated today eventually relapse, and subsequent responses and durations of responses become increasingly shorter.

Ultimately, patients become resistant to chemo-immunotherapy, clinically defined as relapsed within 12 months.

In these patients, the toxicity commonly outweighs the benefit of treatment with chemotherapy.

Autologous CAR T therapy has made significant advances in addressing R/R NHL, and has moved to earlier lines of therapy, as further described below under — "Competition".

Results from the Phase 1 ALLO-501 ALPHA Trial and the Phase 1 ALLO-501A ALPHA2 Trial

On November 29, 2022, we, in collaboration with Servier, announced results from the Phase 1 ALPHA trial of ALLO-501 and from the Phase 1 ALPHA2 trial of ALLO-501A in R/R LBCL at our R&D Showcase.

We conducted an extensive Phase 1 program designed to evaluate and optimize all aspects of our lead product candidate, including the dose and schedule of ALLO-501A and ALLO-647.

In addition, following a review of the Phase 1 program, we determined that our Alloy manufacturing process was associated with robust performance.

Alloy is being deployed in the ongoing Phase 2 ALPHA2 trial.

A single infusion of CAR+ cells with a lymphodepletion regimen consisting of fludarabine (30 mg/m2/day x 3 days) and cyclophosphamide (300 mg/m2/day x 3 days) (standard flu/cy) plus 90 mg of ALLO-647 (Single Dose FCA90) was deemed preferable to two infusions of CAR+ cells (Consolidation Regimen).

In the Consolidation Regimen, ALLO-647 dosing was split into 60 mg and 30 mg prior to the first and second infusion of CAR+ cells.

This finding underscores the importance of optimizing lymphodepletion in allogeneic cell therapy.

Data from the Phase 1 trials of ALLO-501 and ALLO-501A support the ability of a single administration of CAR T cells to generate deep and durable responses.

As of the October 25, 2022 data cutoff, 33 autologous CAR T naïve patients with r/r LBCL were treated with Alloy process material.

Ninety-two percent (92%) of all enrolled patients received investigational product with 100% of infused product manufactured and released as per product specifications.

Patients were able to initiate treatment within two days of enrollment.

Responses in the ALPHA trials were overall durable.

Of the nine patients treated with Alloy process material who achieved a complete response (CR) at six months, eight remained in remission with the longest CR ongoing at 26+ months as of the data cutoff.

Among 12 patients treated with the Single Dose FCA90 regimen, the overall response rate (ORR) was 67% and 58% achieved CRs.

Among the eight patients in the Single Dose FCA90 cohort who had the opportunity to be followed for six months or more, four (50%) were in CR at both six and 12 months.

Alloy Process

(n = 48) All Alloy

(n=33) Consolidation Regimen (n=15) Single Dose FCA90

Results from the Phase 1 ALLO-501 ALPHA Trial and the Phase 1 cema-cel ALPHA2 Trial

On June 3, 2023, we announced long-term follow up data from the Phase 1 ALPHA trial of ALLO-501 and from the Phase 1 ALPHA2 trial of cema-cel in R/R LBCL at the American Society of Clinical Oncology (ASCO) Annual Meeting.

We conducted an extensive Phase 1 program designed to evaluate and optimize all aspects of our lead product candidate, including the dose and schedule of cema-cel and ALLO-647.

The long-term data included an updated analysis of data from 12 CAR T-naïve patients with R/R LBCL who received a single dose of ALLO-501/cema-cel manufactured using the Alloy™ process following a lymphodepletion regimen (FCA90) comprised of fludarabine (30 mg/m2/day x 3 days) and cyclophosphamide (300 mg/m2/day x 3 days) plus ALLO-647 (30 mg/day x 3 days).

The median time from enrollment to the start of therapy was three days and all 12 patients were followed through a minimum of six months (data cutoff April 20, 2023).

The updated data from the Phase 1 trials of ALLO-501 and cema-cel are foundational for our ALPHA3 trial and continue to support the ability of a single administration of allogenic CAR T cells to induce durable complete remissions at a rate similar to approved autologous CD19 CAR T therapies.

Among the 12 patients treated with the single dose FCA90

regimen, the overall response rate (ORR) was 67% and 58% achieved CRs with 42% maintaining CR through month six.

Of the five patients who were in CR at six months, four (80%) remained in CR.

The fifth patient had disease progression at 24 months.

The median duration of response was 23.1 months with three patients remaining in remission for over 24 months and the longest remaining in remission for over 31 months.

Patients Treated with Phase 2 Regimen (n=12)

Overall Response Rate (ORR), n (%)

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6 Month CR Rate, n (%)

12 Month CR Rate, n (%) 8 (21) 8 (28) 4 (27) 4 (50)

The ALPHA Phase 1 trials demonstrated a manageable safety profile.

There were no observed dose limiting toxicities (DLTs) or graft-vs-host disease (GvHD).

Among patients treated with Single Dose FCA90, there was no Grade 3+ cytokine

release syndrome (CRS) or neurotoxicity.

The ALPHA and ALPHA2 Phase 1 trials demonstrated a manageable safety profile and treatment was generally well tolerated with no GvHD and no observed dose limiting toxicities (DLTs).

Among patients treated with single dose FCA90, there was no Grade 3+ CRS or neurotoxicity.

One patient (8%) experienced a Grade 3+ infection and two (17%) experienced prolonged Grade 3+ cytopenia.

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No new Grade 5 events have occurred.

Alloy Process

(n=48) All Alloy

(n=33) Consolidation Regimens

(n=15) Single Dose

Adverse Events of Interest All Grs

n (%) All Grs

CRS 11 (23) 0 8 (24) 0 3 (20) 0 4 (33) 0

All R/R CAR T naïve LBCL

Patients Treated with Phase 2 Regimen

Neurotoxicity

ICANS 1 (2) 0 0 0 0 0 0 0

GvHD 0 0 0 0 0 0 0 0

Infection 25 (52) 9 (19) 19 (58) 5 (15) 8 (53) 3 (20) 8 (67) 1 (8)

Prolonged Gr3+ Cytopenia

Clinical Development Plan

The ALPHA trial is an open-label, Phase 1, single arm, multicenter clinical trial evaluating the safety and tolerability of ALLO-501 in adult patients with R/R LBCL, including DLBCL, or FL.

Second Target Indication:

Chronic Lymphocytic Leukemia (CLL)

CLL is also a hematologic cancer originating from malignant lymphocytes.

Within the United States, annually approximately 20,700 new cases of CLL are estimated to be diagnosed with approximately 4,400 deaths estimated to occur according to 2024 figures from the American Cancer Society.

Targeted therapy can be used to treat CLL, including treatment with Bruton tyrosine kinase inhibitors (BTKi) or B-cell lymphoma 2 inhibitors (BCL2i).

Although such frontline therapies can be effective in achieving a remission, CLL remains incurable, and the disease will likely relapse and require further line(s) of therapy.

While recent autologous CD19 CAR T data has been a positive step for patients with R/R CLL, outcomes in CLL following CAR T treatment have yet to meet expectations set in R/R LBCL.

This is likely due in part to T cell dysfunction and the potential for high circulating tumor burden in CLL, making the isolation of functional T cells for autologous CAR T manufacturing difficult.

We believe that our AlloCAR T™ products, such as cema-cel which is derived from healthy donor cells, could potentially create a clinically meaningful advance for these late-stage CLL patients, with a one-time dose and simpler administration and logistics.

Clinical Development Plan - Non-Hodgkin Lymphoma (NHL)

We are the sponsor of the ALPHA trial of ALLO-501 and ALPHA2 trial of cema-cel, each for patients with R/R NHL or CLL.

The ALPHA trial is a Phase 1 clinical trial of ALLO-501 in patients with R/R LBCL and R/R FL.

We completed accrual in the ALPHA trial in 2021 and are following patients as part of long-term follow-up.

The ALPHA2 trial is an open-label, Phase 1/2, single arm, multicenter clinical trial evaluating the safety and efficacy of ALLO-501A in adult patients with R/R large B-cell lymphoma, including DLBCL, or transformed FL.

Cell kinetics and pharmacodynamics of ALLO-501A are evaluated as secondary and exploratory objectives, respectively.

The Phase 1 portion of the ALPHA2 trial was designed to assess the safety and tolerability at increasing dose levels of ALLO-501A and consolidation of ALLO-501A dosing, in order to identify the recommended doses and schedule of ALLO-501A and the lymphodepletion regimen for use in the Phase 2 portion of the trial.

In the fourth quarter of 2022, we initiated the Phase 2 portion of the ALPHA2 trial in patients with R/R LBCL.

The single-arm Phase 2 ALPHA2 trial is utilizing a single dose of ALLO-501A (120 million CAR+ cells) with the FCA90 lymphodepletion regimen.

The ALPHA2 trial will enroll approximately 100 patients who have received at least two prior lines of therapy and have not received prior anti-CD19 therapy.

The primary endpoint of this trial is ORR, and the key secondary endpoint is duration of response.

We expect to complete enrollment in the trial in the first half of 2024.

We are also preparing a Phase 3 trial of ALLO-501A in an earlier line of therapy for LBCL, which we expect to initiate in the first half of 2024.

We are also advancing the EXPAND trial of ALLO-647, which is expected to enroll approximately 70 patients with R/R LBCL and is intended to demonstrate the overall contribution of ALLO-647 to the benefit to risk ratio of the lymphodepletion regimen for ALLO-501A.

Patients will be randomized to receive the same single 120 million CAR+ cell dose of ALLO-501A as in the ALPHA2 trial and either lymphodepletion with fludarabine and cyclophosphamide (control arm) or the lymphodepletion regimen of the ALPHA2 trial, inclusive of ALLO-647 (active arm).

We expect the EXPAND trial to open to enrollment early in the second quarter of 2023.

Assuming favorable outcomes and subject to FDA discussions, we plan to seek FDA approval of ALLO-501A and ALLO-647 on the basis of the ALPHA2 trial and the EXPAND companion trial.

Anti-BCMA Development Program

BCMA is a member of the tumor necrosis factor receptor family and is selectively expressed on immunoglobulin-producing plasma cells, including malignant plasma cells (myeloma cells).

We believe BCMA is an appropriate target for the treatment of multiple myeloma.

Autologous anti-BCMA targeted CAR T therapies have shown promising results in clinical trials and have been approved by the FDA for adult patients with R/R multiple myeloma, as further described below under "—Competition".

ALLO-715 is our first anti-BCMA allogeneic CAR T cell product candidate assessed in the clinic.

ALLO-715 is manufactured to express a CAR that is designed to target BCMA and gene edited to lack TCRα and CD52 to minimize the risk of GvHD and enable a window of persistence in the patient when dosed in combination with ALLO-647.

In addition, rituximab

recognition domains, as an off-switch, have been incorporated in between the scFv and the linker domain.

We are conducting a Phase 1 clinical trial (the UNIVERSAL trial) of ALLO-715 in adult patients with R/R multiple myeloma.

Our next-generation version of ALLO-715, known as ALLO-605, incorporates our TurboCAR technology to allow cytokine signaling to be engineered selectively into CAR T cells.

TurboCARs have shown the ability to improve the potency and persistence of the CAR T cells and to delay exhaustion of the CAR T cells in preclinical models.

ALLO-605 uses a constitutive cytokine signaling domain and a rituximab-mediated off-switch, as illustrated below.

We initiated the Phase 1 clinical trial (the IGNITE trial) of ALLO-605 in mid-2021.

Target Indication:

Multiple Myeloma

Multiple myeloma is a hematological malignancy that is characterized by uncontrolled expansion of bone marrow plasma cells.

There will be an estimated 35,730 new cases of multiple myeloma and 12,590 deaths from multiple myeloma in 2023 in the United States according to the American Cancer Society.

Multiple myeloma predominantly affects the elderly, with 14 times more patients diagnosed at age 65 and over than those diagnosed under the age of 65.

For patients under the age of 70 with no comorbidities, autologous stem cell therapy is the preferred option to provide a durable response.

For transplant ineligible patients, immunomodulatory drugs (Revlimid, Pomalyst, Thalomid) and proteasome inhibitors (Velcade, Kyrprolis, Ninlaro), often used in combination with one another, have displaced older cytotoxic agents as the mainstay of treatment.

More recently, several new drugs with novel mechanisms (Darzalex, Empliciti, Farydak, Xpovio) have been approved for multiple myeloma, however none of these novel treatments is considered as curative.

Despite the introduction of newer therapies, a majority of patients are expected to relapse and the unmet need in patients with R/R myeloma remains high.

In patients who have developed progressive disease following exposure to all five classes of non-cytotoxic therapies, options are limited.

Cytotoxic chemotherapy-containing regimens are reserved for fit patients, are given as continuous infusions and are associated with significant toxicity and generally limited efficacy.

The single agent selexinor (Xpovio) has been studied as a single agent in patients with disease refractory to all five classes of novel agents and is associated with an ORR of 26%, a median duration of response of 4.4 months and toxicity that required discontinuation of treatment in 18% of patients.

Trials of anti-BCMA therapies including bispecific antibodies and autologous CAR T cell therapies have shown significant promise in multiple myeloma with reported CR rates that are substantially higher in patients with R/R myeloma.

There are two autologous CAR T cell therapies and one bispecific antibody currently commercially available.

Results from the Phase 1 ALLO-715 UNIVERSAL Trial

On November 29, 2022, we announced results from the Phase 1 UNIVERSAL trial of ALLO-715 in patients with R/R multiple myeloma.

Dose expansion cohorts comprised of a single dose of ALLO-715 (320 million CAR+ cells) and either FCA39 lymphodepletion (standard flu/cy plus 39 mg of ALLO-647) or FCA60 lymphodepletion (standard flu/cy plus 60 mg of ALLO-647) demonstrated substantial and durable responses.

Importantly, 92% of all enrolled patients received investigational

product with 100% of infused product manufactured and released as per product specifications.

Patients were able to initiate treatment within five days of enrollment and no bridging therapy was required.

Through a median follow-up of 14.8 months as of the October 11, 2022 data cutoff, the ORR was 67% in the FCA60 cohort and the very good partial response or better rate (VGPR+) was 42%.

All VGPR+ were minimal residual disease (MRD) negative.

The median duration of response was 9.2 months, with the longest ongoing response at 24 months.

Expansion Cohorts

LD Regimen Total

(n=23*) FCA39

ORR*, n (%) 15 (65) 7 (64) 8 (67)

VGPR+ rate, n (%) 11(48) 6 (54) 5 (42)

CR/sCR rate, n (%) 5 (22) 3 (27) 2 (17)

Median DOR 8.3 8.3 9.2

* Five patients with best responses ranging from stable disease to partial response were not included due to limited follow-up.

Safety profile was manageable with low-grade and reversible neurotoxicity and no GvHD.

In the expansion cohorts, there was low use of tocilizumab (32%) and steroids (25%).

Eight patients (29%) experienced Grade 3+ infections and prolonged Grade 3+ cytopenias.

As previously reported, one Grade 5 event occurred in the expansion cohorts and no new Grade 5 events have occurred.

Expansion Cohorts

Adverse Events of Interest All Grades

n (%) Grade 3+

CRS 19 (68) 1 (4)

Neurotoxicity 17 (61) 0

ICANS 1 (4) 0

Infection 19 (68) 8 (29)

Prolonged Gr3+ Cytopenia — 8 (29)

Clinical Development Plan

The UNIVERSAL and IGNITE trials are open-label, Phase 1, single-arm, multicenter clinical trials evaluating the safety and tolerability of ALLO-715 and ALLO-605, respectively, in adult patients with R/R multiple myeloma.

The safety of ALLO-647, cell kinetics, pharmacodynamics, and efficacy are evaluated as secondary objectives.

In the first half of 2021, the UNIVERSAL trial initiated the evaluation of ALLO-715 in combination with nirogacestat.

We dosed an initial set of patients in the combination cohort and made the decision not to advance ALLO-715 in combination with nirogascestat into dose expansion cohorts.

We are currently reviewing and optimizing the manufacturing process for our BCMA program in order to improve and obtain more consistent clinical results and are not enrolling patients in the UNIVERSAL and IGNITE trials at this time.

Anti-CD70 Development Program

CD70 is an antigen selectively expressed on several types of cancer cells, with strong expression in ccRCC and limited off-tumor expression.

The ALPHA2 trial was initiated as a Phase 1/2 clinical trial for cema-cel in the second quarter of 2020.

The Phase 1 portion of the ALPHA2 trial was designed to assess the safety and tolerability at increasing dose levels of cema-cel in patients with R/R LBCL.

In the fourth quarter of 2022, we proceeded to the Phase 2 portion of the ALPHA2 trial in adult patients with R/R LBCL.

We are also sponsoring the EXPAND trial of ALLO-647, which was intended to demonstrate the overall contribution of ALLO-647 to the benefit to risk ratio of the lymphodepletion regimen for cema-cel.

In January 2024 we announced that we would deprioritize the ALPHA2 R/R LBCL and EXPAND trials to focus on our ALPHA3 trial, which will seek to embed cema-cel as part of a 1L consolidation strategy.

We have deprioritized the ALPHA2 R/R LBCL trial primarily because the ALPHA3 trial, if successful, could significantly impact the need for cell therapy in later lines of treatment, including the third line (3L) patients being studied in our ALPHA2 trial.

The ALPHA3 trial will be an open-label, Phase 2, multicenter clinical trial evaluating the safety and efficacy of cema-cel in adult patients with

LBCL who have completed R-CHOP and have attained a remission, but who test positive for MRD.

The ALPHA3 trial will randomize approximately 230 patients who achieve a complete or partial response to 1L therapy, but who test positive for MRD at their end-of-therapy PET/CT assessment.

The patients will be randomized to either treatment with cema-cel or the current standard of care, which is observation.

The design, with a primary endpoint of EFS, will initially include two lymphodepletion arms (one with standard fludarabine and cyclophosphamide plus ALLO-647 and one without ALLO-647).

One lymphodepletion arm will be discontinued following a planned interim analysis in mid-2025 designed to select the most appropriate regimen for this patient population.

The ALPHA3 trial will leverage an investigational diagnostic test developed by Foresight Diagnostics to identify patients who have MRD at the completion of 1L chemoimmunotherapy.

Although 1L R-CHOP is curative for many with LBCL, as noted above, approximately 30% of patients treated will relapse.

Under the current standard of care, there is no way to determine which patients are at greater risk of relapse after initially responding to 1L treatment, and so the standard of care has been simply to “watch and wait” for the disease to relapse.

Foresight Diagnostics, however, has developed a liquid biopsy testing platform for the measurement of MRD.

Based on Foresight Diagnostics’ published data, we believe that the Foresight Diagnostics’ assay is highly sensitive and predictive of which patients are likely to relapse.

By incorporating the Foresight Diagnostics assay into our ALPHA3 trial design, we believe that we can identify the patient population most at risk for relapse and treat those patients with cema-cel.

ALPHA3 takes advantage of cema-cel as a one-time, off-the-shelf treatment that can be administered immediately upon discovery of MRD following six cycles of R-CHOP, potentially positioning cema-cel to become the standard “7th cycle” of frontline treatment available to all eligible patients with MRD.

ALPHA3 builds on our belief that administration of CAR T therapies to patients with low disease burden improves both safety and efficacy outcomes.

Cema-cel’s Phase 1 safety profile, with low rates of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), already permits its use in the outpatient setting in R/R patients and may further improve in patients with no radiological evidence of disease.

Start-up activities for ALPHA3 are underway and we plan to initiate the trial in mid-2024.

Assuming favorable outcomes and subject to FDA discussions, we plan to seek FDA approval of cema-cel and ALLO-647 on the basis of the ALPHA3 trial.

Clinical Development Plan - Chronic Lymphocytic Leukemia (CLL)

We have initiated a new CLL cohort as part of our ALPHA2 trial.

This new cohort is a Phase 1b cohort that is a single-arm, open-label, multicenter study evaluating the safety and efficacy of cema-cel following lymphodepletion with fludarabine/cyclophosphamide and ALLO-647 in patients with R/R CLL/SLL.

This trial will include patients with high-risk CLL treated with ≥1 prior line of BTKi-based therapy or those treated with ≥2 prior lines of therapy, including a BTKi and BCL2i.

The primary endpoint of the phase 1b portion of this study is safety.

Secondary endpoints include overall response rate, duration of response, time to response, and progression-free survival per investigator assessment.

Up to approximately 40 patients may be enrolled in sites across the United States.

This study leverages currently active ALPHA2 trial sites in the U.S.

which should allow it to advance quickly.

We opened enrollment in the first quarter and anticipate initial data by year end 2024.

Anti-CD70 Oncology Development Program

CD70 is an antigen expressed on several types of cancer cells, with strong expression in RCC and limited off-tumor expression.

CD70 is selectively expressed in a portion of other solid tumors and blood cancers.

While CD70 can be expressed on activated T cells, ALLO-316 was associated with minimal or no fratricide in preclinical studies, meaning that ALLO-316 cells did not mediate the targeted killing of other ALLO-316 cells.

Accordingly, we believe progressing allogeneic CAR T cell therapies directed against CD70 could be promising in solid tumor indications as well as hematological malignancies.

ALLO-316 is manufactured to express a CAR that is designed to target CD70 and gene edited to lack TCRα and CD52 to minimize the risk of GvHD and enable a window of persistence in the patient when dosed in combination with ALLO-647.

In addition, rituximab and CD34 recognition domains have been incorporated in between the scFv and the linker domain, as

illustrated below.

The rituximab recognition domains allow elimination of cells with rituximab in the event that silencing of CAR T cell activity is desired.

Accordingly, we believe progressing allogeneic CAR T cell products directed against CD70 could be promising in solid tumor indications as well as hematological malignancies.

ALLO-316 is manufactured to express a CAR that is designed to target CD70 and gene edited to lack expression of the TCR and CD52 to both minimize the risk of GvHD and to enable use of CD52 monoclonal antibodies to permit a window of persistence of CAR T cells in the patient .

In addition, rituximab and CD34 recognition domains have been incorporated in between the scFv and the linker domain, as illustrated below.

The rituximab recognition domains allow targeting of cells with rituximab in the event that silencing of CAR T cell activity is desired.

The CD34 domain confers recognition by an anti-CD34 antibody, and may be used as a surface marker to monitor ALLO-316 in patients by flow cytometry.

In the first half of 2021, we initiated a Phase 1 clinical trial (the TRAVERSE trial) of ALLO-316 in adult patients with advanced or metastatic ccRCC.

In the first half of 2021, we initiated Phase 1 TRAVERSE clinical trial of ALLO-316 in adult patients with advanced or metastatic ccRCC.

Lead Target Indication:

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sunitinib) represented a first-line standard for over a decade, these therapies have been quickly supplanted by combination therapies incorporating PD-1 immune-checkpoint inhibition as the backbone.

The combination of VEGF and immune check-point inhibitors, such as axitinib and pembrolizumab, is often used in the first line setting and has shown a median progression-free survival of 15.1 months with an ORR of 59.3% and CR rate of 5.8%.

Patients who progress on immune checkpoint-based combination therapies can be treated with agents including cabozantinib, Lenvatinib with everolimus or other therapies.

The combination of VEGF and immune check-point inhibitors, such as axitinib and pembrolizumab, respectively, is often used in the first line setting and has shown a median progression-free survival of 15.1 months with an ORR of 59.3% and CR rate of 5.8%.

Patients who progress on immune checkpoint-based combination therapies can be treated with agents including cabozantinib, lenvatinib with everolimus, tivozanib, belzutifan or other therapies.

Results from the Phase 1 ALLO-316 TRAVERSE Trial

On November 29, 2022, we announced preliminary results from the Phase 1 TRAVERSE trial of ALLO-316 in patients with advanced or metastatic RCC who have progressed on or intolerant to standard therapies, including an immune checkpoint inhibitor and a VEGF-targeting therapy.

Initial data from this trial has demonstrated the promise of an allogeneic CAR T product candidate to treat CD70 expressing RCC with ALLO-316 inducing anti-tumor activity.

Observed anti-tumor activity was largely confined to patients with CD70 expressing tumors.

As of the data extract date of November 17, 2022, in the nine patients with tumors known to express CD70, the disease control rate (DCR) was 100% including three patients who achieved a partial response (PR) (two confirmed and one unconfirmed, with the longest response lasting until month eight).

On April 17, 2023, we announced interim results from the Phase 1 TRAVERSE trial of ALLO-316 in patients with advanced or metastatic RCC who have progressed on or who are intolerant to standard therapies, including an immune checkpoint inhibitor and a VEGF-targeting therapy.

The interim results provide proof-of-concept demonstrating the promise of an allogeneic CAR T product candidate to treat CD70-expressing RCC with ALLO-316.

As of the data extract date of March 23, 2023, in the ten patients with tumors known to express CD70, the disease control rate (DCR) was 100% including three patients who achieved a partial response (PR) (two confirmed and one unconfirmed, with the longest response lasting until month eight).

Cell expansion in patients with CD70 positive disease was robust and there was a trend toward greater tumor shrinkage in patients with high CD70 expression.

(n=17) CD70+ Patients

ORR, n (%) 3 (18) 3 (33)

DCR, n (%) 14 (82) 9 (100)

PR, n (%) 3 (18) 3 (33)

ALLO-316 has demonstrated a generally manageable safety profile with no GvHD.

One dose limiting toxicity of auto-immune hepatitis occurred in the second dose level.

CD70+ Patients

Overall Response Rate (ORR), n (%)

Disease Control Rate (DCR), n (%)

Partial Response (PR), n (%)

There were 19 patients evaluable for safety, and the data demonstrated an adverse event profile generally consistent with autologous CAR T therapies.

One dose limiting toxicity of Grade 3 auto-immune hepatitis occurred in the second dose level.

Grade 3+ prolonged cytopenia was observed in three patients (18%).

CRS was all low grade with the exception of one case of Grade 3 CRS.

Neurotoxicity was low grade, reversible and seen in three patients (18%).

No grade 5 events have occurred.

CRS 11 (65) 1 (6)

Neurotoxicity, which is now defined more broadly, was generally low grade and reversible with most events being fatigue or headache.

There were no cases of ICANs.

Infections occurred in eight patients of which four were Grade 3+ including one Grade 5 respiratory failure due to Covid-19 infection deemed unrelated to study treatment.

Grade 3+ prolonged cytopenia was observed in three patients (16%).

There were no cases of GvHD.

Infusion-Related Reaction

Neurotoxicity

Infection 9 (53) 5 (30)

Prolonged Gr3+ Cytopenia

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The trial is now deploying the IVD assay for the purposes of identifying patients most likely to benefit from ALLO-316.

TRAVERSE will continue to explore varying cell dose and lymphodepletion regimens, including FC and FCA in CD70 positive RCC patients.

Subject to ongoing results in the TRAVERSE trial, we intend to complete planned dose exploration and initiate expansion cohort enrollment in 2023.

We may also investigate ALLO-316 for other CD70 expressing solid tumors and hematologic indications or in combination with other anticancer therapies such as immune checkpoint inhibitors.

TRAVERSE will continue to explore varying cell dose and lymphodepletion regimens in CD70 positive RCC patients.

During the advancement of the TRAVERSE trial with ALLO-316, we have observed allogeneic CAR T cell expansion and persistence driven by CD70 CAR that allows elimination of alloreactive host lymphocytes.

This biology has brought the potential for clinical efficacy not often seen in patients with R/R RCC but has also resulted in a hyperinflammatory response in some patients as CD70 CAR T cells expand and persist.

Leveraging recent advances in the management of hyperinflammation following autologous CAR T administration, we have developed a diagnostic and treatment algorithm similar to what our management team previously helped develop for CRS and ICANS associated with autologous CAR T.

This algorithm may mitigate the treatment-associated hyperinflammatory response without compromising the CAR T function needed to eradicate solid tumors.

We have recently implemented a protocol amendment to further maximize the benefit-risk of ALLO-316 in patients with CD70+ RCC.

The next update from this trial is planned for a medical forum in second quarter 2024 and will discuss the safety algorithm that is believed to be an important advance for the TRAVERSE trial.

A more robust data update from the ongoing trial with the updated protocol is planned for later in 2024.

Anti-CD19/CD70 Autoimmune Disease Development Program

Autoimmune disease (AID) can affect organs throughout the body.

B cells and T cells are two key components of the immune system, each playing distinct roles in the body’s defense against pathogens and in maintaining immune tolerance.

Effective collaboration between B cells and T cells results in the sustained production of autoantibodies, which are antibodies that mistakenly target and react with a person’s own tissues or organs resulting in AID.

Autoantibodies are critical to the pathogenesis of many AIDs.

As a result, we believe that disruption of the B cell-T cell network could lead to an effective treatment of AIDs.

As noted above, CD19 is an antigen expressed on the surface of B cells, including pathogenic autoreactive B cells.

Activated T cells, which upregulate CD70, induce sustained production of autoantibodies by B cells from patients affected by AID.

Moreover, CD70 expression is elevated on T cells of patients in certain AIDs, suggesting a pathogenic role for CD70+ T cells in AID.

Accordingly, we believe progressing allogeneic CAR T cell therapies directed against CD19 and CD70 could be promising in AID indications.

ALLO-329 is manufactured to express two independent CARs designed to target CD19 and CD70.

As illustrated below, a single transgene encoding both the CD19 CAR and the CD70 CAR is targeted for insertion into the TRAC locus using site-specific integration, resulting in uniform expression of both CARs and the lack of TCR expression.

ALLO-329 is designed to mediate the depletion of CD19+ B cells and pathogenic T cells that upregulate CD70 expression.

CD70 is also upregulated on activated B cells and alloreactive lymphocytes.

Therefore, ALLO-329 can also target pathogenic CD70+ B cells and prevent allorejection by eliminating CD70+ alloreactive lymphocytes in the patients.

The anti-rejection features of ALLO-329 may help reduce or eliminate the need for lymphodepletion prior to treatment with ALLO-329.

We are developing ALLO-329, an allogeneic CAR T cell product candidate targeting both CD19 and CD70 for the treatment of certain autoimmune diseases.

Inclusion of an anti-CD70 CAR in ALLO-329 is designed to reduce or eliminate the need for standard chemotherapy by preventing premature rejection while also targeting CD70+ activated lymphocytes, which may play a direct role in AID pathogenesis.

Initiation of this Phase 1 trial with ALLO-329 is expected in early 2025.

Future Opportunities

Moving forward, we plan to utilize our allogeneic platform to pursue additional targets of interest.

Currently, we remain focused on our four key programs described above.

As we advance those programs, we may seek to utilize our allogeneic platform to pursue additional targets of interest, particularly through strategic partnerships.

These include the additional targets currently in our pipeline as well as other targets that might be validated in the future.

For example, we are developing allogeneic CAR T cell product candidates targeting FLT3 for the treatment of AML (ALLO-819), DLL3 for the treatment of small cell lung cancer and Claudin 18.2 for the treatment of gastric and pancreatic cancer.

We also plan to investigate the potential to enhance our platform using next-generation technologies such as TurboCARs, renewable cell sources, site-specific integration, multi-specific CARs and other technology related to enhancing specificity and avoiding immune rejection.

• Next-generation anti-rejection technology:

We are investigating additional ways, beyond our existing anti-CD52 antibody technology, to prevent premature patient immune rejection of our allogeneic CAR T cells.

We are exploring ways to engineer allogeneic CAR T cells to escape detection from the patient immune system, such as through our research collaboration with Antion Biosciences SA (Antion).

We are also exploring engineering allogeneic CAR T cells with mechanisms to attack certain patient immune cells that would otherwise lead to rejection.

For instance, based on initial data from the TRAVERSE trial that showed high CAR T cell expansion in patients, we are exploring utilizing an anti-CD70 CAR, which we call Dagger, to recognize and destroy allo-reactive host immune cells that would otherwise be capable of rejecting the allogeneic CAR T cells, which could provide enhanced persistence of the allogeneic CAR T cells.

• TurboCARs .

We are investigating multiple constructs designed to mimic cytokine signaling selectively within CAR T cells, a technology platform that we call “TurboCARs”.

Mimicking cytokine signaling within a CAR T cell could enhance the proliferative potential, migratory behavior, activation status and killing activity of cells.

Such modulation may enhance the anti-tumor activity and durability of CAR T cells without affecting non-engineered immune cells.

believe TurboCARs may also allow for reduced CAR T cell dose requirements and greater impact in overcoming exhaustion in solid tumor environments.

• Renewable Cell Source.

In November 2019, we entered into a Collaboration and License Agreement (the Notch Collaboration Agreement) with Notch Therapeutics Inc.

(Notch), pursuant to which Notch has granted to us an exclusive, worldwide, royalty-bearing, license to certain Notch intellectual property to develop and commercialize gene-edited T cell and/or natural killer cell products from induced pluripotent stem cells (iPSCs) directed at certain CAR targets for initial application in NHL, ALL and multiple myeloma.

We believe iPSCs may provide renewable starting material for our allogeneic CAR T cell product candidates that could allow for improved efficiency of gene editing, greater scalability of supply, product homogeneity and more streamlined manufacturing.

• Site-Specific Integration .

Using a combination of gene-editing technology and homologous recombination technology we can potentially integrate the CAR expressing DNA into specific target genes within the T cell DNA.

Such site-specific integration may allow the CAR or other transgenes to be introduced into T cells in a more homogeneous manner, allowing a more uniform and controlled expression of the proteins, with the goal of generating CAR T cell products that behave in a more consistent and predictable manner.

It may also allow longer sequences of DNA to be inserted into the T cell, allowing for the expression of genes that would not otherwise be feasible with viral based gene insertion.

• Multi-specific CARs.

We are investigating the utility of a single cell product targeting multiple antigens.

This may be accomplished by including two antigen binding domains with different specificity in a single polypeptide encoding the CAR or in two separate polypeptides each encoding a CAR with different antigen specificity.

• Increasing tumor specificity of targets:

We are investigating technology to localize activity of an allogeneic CAR T cell to the tumor microenvironment in an effort to extend specificity and therefore safety of CAR T cells.

We believe this approach may be particularly promising for solid tumor targets that are also expressed on normal tissues.

In addition, we continually survey the scientific and industry landscape for opportunities to license, partner or acquire technologies that may help us advance current or new T cell therapies for the benefit of patients.

For example, we have been developing allogeneic CAR T cell product candidates targeting B-cell maturation antigen (BCMA) for treatment of multiple myeloma (ALLO-715), FLT3 for the treatment of acute myeloid leukemia (ALLO-819), DLL3 for the treatment of small cell lung cancer (ALLO-213), and Claudin 18.2 for the treatment of gastric and pancreatic cancer (ALLO-182).

Our Manufacturing Strategy

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We plan to continue to invest in process science, product characterization and manufacturing to continuously improve our manufacturing processes, production and supply chain capabilities over time.

Our product candidates are designed and manufactured via a platform comprised of defined unit operations and technologies.

The process is gradually developed from small to larger scales, incorporating compliant procedures to create cGMP conditions.

Our product candidates are designed and manufactured via platforms comprised of defined unit operations and technologies.

Processes are developed from small to larger scales, incorporating compliant procedures to create cGMP conditions.

Although we have a platform-based manufacturing model, each product is unique and for each new product candidate, a developmental phase is necessary to individually customize each engineering step and to create a robust procedure that can later be implemented in a cGMP environment to ensure the production of clinical batches.

This work is performed in our research and development environment to evaluate and assess variability in each step of the process in order to define the most reliable production conditions.

Our cell-based product candidates are currently manufactured in the United States by a CMO, and we manage all other aspects of the supply, including planning, CMO oversight, disposition and distribution logistics.

The CMO that is manufacturing our clinical supply is subject to cGMP requirements, using qualified equipment and materials.

We also utilize separate third party contractors to manufacture cGMP raw materials that are used for the manufacturing of our product candidates, such as viral vectors that are used to deliver the applicable CAR gene into the T cells.

This work is performed in our process development environment to evaluate and assess variability in each step of the process in order to define the most reliable production conditions.

Historically, we have used a CDMO to manufacture our cell-based product candidates in the United States, and we managed all other aspects of the supply, including planning, CDMO oversight, disposition and distribution logistics.

The CDMO is subject to cGMP requirements, using qualified equipment and materials.

We also have utilized separate third-party contractors to manufacture cGMP raw materials that are used for the manufacturing of our product candidates, such as viral vectors that are used to deliver the applicable CAR gene into the T cells.

We believe all materials and components utilized in the production of the cell line, viral vector and final T cell product are available from qualified suppliers and suitable for pivotal process development in readiness for registration and commercialization.

In addition, in February 2019, we entered into a lease for approximately 118,000 square feet to develop a state-of-the-art cell therapy manufacturing facility in Newark, California that we call Cell Forge 1 (CF1).

We are phasing the build-out of CF1, and completed the build-out of the majority of the facility at the end of 2020.

We initiated cGMP manufacturing of ALLO-501A in 2021 at CF1 that did not utilize the Alloy process.

After a review of the Phase 1 program and data in 2022, we determined that the Alloy manufacturing process associated with robust clinical performance.

We are currently manufacturing ALLO-501A using the Alloy process at our CMO.

We are currently assessing the product candidates for manufacturing at CF1.

Introducing product manufactured at CF1 into an ongoing clinical trial will require that we meet certain regulatory conditions, such as establishing comparability with the product candidates manufactured at our CMO, and our inability to meet such conditions would result in investment of additional resources and delay of our clinical trial timeline.

We expect to continue to rely on our CMO and may rely on CMOs and other third parties for the manufacturing and processing of our product candidates in the future.

We also utilize a CMO in the United States for the manufacture and supply of ALLO-647 and we plan to continue to rely on the CMO for future production of ALLO-647.

In February 2019, we entered into a lease for approximately 118,000 square feet to develop a state-of-the-art cell therapy manufacturing facility in Newark, California that we call Cell Forge 1 (CF1).

We completed the intended build-out of the majority of the facility at the end of 2020.

We are currently utilizing CF1 for clinical manufacturing of our product candidates.

We continue to rely upon certain third-party contractors to manufacture cGMP raw materials.

Introducing product manufactured at CF1 into an ongoing clinical trial will require that we meet certain regulatory conditions, such as establishing comparability with the product candidates manufactured at our CDMO, and our inability to meet such conditions would result in investment of additional resources and delay of our clinical trial timeline.

Although we are utilizing CF1 for clinical manufacturing, we may continue to rely on CDMOs and other third parties for the manufacturing and processing of our product candidates in the future.

We also utilize a CDMO in the United States for the manufacture and supply of ALLO-647 and we plan to continue to rely on the CDMO for future production of ALLO-647.

We believe the use of contract manufacturing and testing for our first clinical product candidates has allowed us to rapidly prepare for clinical trials in accordance with our development plans.

We expect third-party manufacturers will be capable of providing and processing sufficient quantities of our product candidates to meet anticipated clinical trial demands.

We plan to create a robust supply chain with redundant sources of supply comprised of both internal and external infrastructure.

We plan to maintain a robust supply chain with redundant sources of supply comprised of both internal and external infrastructure.

We expect CF1 and third-party manufacturers will be capable of providing and processing sufficient quantities of our product candidates to meet anticipated clinical trial demands.

Strategic Agreements

On December 14, 2020, we entered into a License Agreement with Allogene Overland Biopharm (CY) Limited, a joint venture established by us and Overland Pharmaceuticals (CY) Inc., pursuant to a Share Purchase Agreement, dated December 14, 2020, for the purpose of developing, manufacturing and commercializing allogeneic CAR T cell therapies for patients in greater China, Taiwan, South Korea and Singapore.

We have also entered into multiple additional strategic agreements and collaborations, including an Asset Contribution Agreement with Pfizer (the Pfizer Agreement), a License Agreement with Cellectis (the Cellectis Agreement), the Servier Agreement, the Notch Collaboration Agreement, and a License and Collaboration Agreement with Antion.

On December 14, 2020, we entered into a License Agreement with Allogene Overland Biopharm (CY) Limited (Allogene Overland), a joint venture established by us and Overland Pharmaceuticals (CY) Inc., pursuant to a Share Purchase Agreement, dated December 14, 2020, for the purpose of developing, manufacturing and commercializing allogeneic CAR T cell therapies for patients in greater China, Taiwan, South Korea and Singapore.

We have also entered into multiple additional strategic agreements and collaborations, including an Asset Contribution Agreement with Pfizer (the Pfizer Agreement), a License Agreement with Cellectis (the Cellectis Agreement), the Servier Agreement, a Collaboration and License Agreement (the Notch Agreement) with Notch Therapeutics Inc.

(Notch), a License and Collaboration Agreement with Antion, and a Strategic Collaboration Agreement with Foresight Diagnostics.

For additional information regarding our significant agreements, see Note 7 to our consolidated financial statements appearing elsewhere in this Annual Report.

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For our lead programs, our patent rights are generally composed of patents and pending patent applications that are solely owned by us, co-owned with Servier, co-owned with Cellectis, exclusively licensed from Pfizer, exclusively licensed from Servier, or exclusively licensed from Cellectis.

Our patent portfolio includes protection for our clinical-stage product candidates, ALLO-501, ALLO-501A, ALLO-715, ALLO-605 and ALLO-316, as well as our research-stage candidates.

With respect to ALLO-501 and ALLO-501A, we have an exclusive license from Servier to patent rights in the United States covering compositions of matter of and methods of making and using ALLO-501 and ALLO-501A.

Our patent portfolio includes protection for our clinical-stage product candidates, ALLO-501, cema-cel, ALLO-715, ALLO-605 and ALLO-316, as well as our research-stage candidates.

With respect to ALLO-501 and cema-cel, we have an exclusive license from Servier to patent rights in the United States covering compositions of matter of and methods of making and using ALLO-501 and cema-cel.

With respect to ALLO-715, ALLO-605 and ALLO-316, we have an exclusive license from Pfizer to patent rights covering ALLO-715, ALLO-605, and ALLO-316 in the United States and in foreign jurisdictions.

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We also have patent rights to the TurboCAR™ technology solely owned by us, including technology that covers the TurboCAR™ construct that is part of ALLO-605.

More generally, our patent portfolio and filing strategy is designed to provide multiple layers of protection by pursuing claims directed toward:

More generally, our patent portfolio and filing strategy is designed to provide multiple layers of protection by pursuing claims directed toward, for example:

(1) antigen binding domains directed to the targets of our product candidates;

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In February 2021, BMS obtained FDA approval for its anti-CD19 autologous T cell therapy, Breyanzi® for the treatment of adults with 3 rd -line LBCL.

Breyanzi’s label was extended to 2 nd -line LBCL in June 2022.

The label of Breyanzi® label was extended to 2 nd -line LBCL in June 2022.

Autologous cell therapies directed at BCMA have been commercialized by BMS and Jannsen, a Johnson & Johnson company.

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received FDA approval of Abecma®, an anti-BCMA autologous T cell therapy, for the treatment of adult patients with multiple myeloma who have received at least four prior therapies.

Jannsen and partner Legend Bio received approval for Carvykti, an anti-BCMA autologous T cell therapy, for the same indication in

February 2022.

Jannsen and partner Legend Bio received approval for Carvykti®, an anti-BCMA autologous T cell therapy, for the same indication in February 2022.

Both Abecma® and Carvykti® have succeeded in pivotal trials in earlier lines of R/R myeloma and are expected to gain label extensions into this market.

Autologous T cell therapies are being developed by a number of additional companies, including but not limited to 2seventy bio, Inc., Adaptimmune Therapeutics PLC, Alaunos Therapeutics, Inc., Arcellx, Inc., Arsenal Biosciences, Inc., Autolus Therapeutics plc, Eureka Therapeutics, Inc., Gilead Sciences, Inc., Gracell Biotechnologies, Inc., ImmPACT Bio, USA Inc., Instil Bio, Inc., Iovance Biotherapeutics, Inc., Legend Biotech Corp., Mustang Bio, Inc., Novartis International AG, Pact Pharma, Inc., TCR² Therapeutics Inc., Tessa Therapeutics, Ltd., Triumvira Immunologics, and TScan Therapeutics, Inc.

Allogeneic T cell therapies have yet to receive FDA approval though the number of companies developing allogeneic product candidates is substantial.

These include ArsenalBio, AstraZeneca, plc, Atara Biotherapeutics, Inc., Beam Therapeutics, Inc., Caribou Biosciences, Inc., CRISPR Therapeutics AG, Editas Medicine, Inc., Fate Therapeutics, Inc., Gilead Sciences, Inc., Gracell Biotechnologies Inc., Intellia Therapeutics, Inc., Legend Biotech Corp., Poseida Therapeutics, Inc., Precision Biosciences, Inc., Sana Biotechnology, Inc., and Tessa Therapeutics Ltd.

Eureka Therapeutics, Inc., Galapagos NV, Gilead Sciences, Inc., Gracell Biotechnologies, Inc., ImmPACT Bio, USA Inc., Instil Bio, Inc., Iovance Biotherapeutics, Inc., Legend Biotech Corp., Mustang Bio, Inc., Novartis International AG, Triumvira Immunologics, and TScan Therapeutics, Inc.

Autologous CAR T therapy has made significant advances in addressing R/R NHL, and has moved to earlier lines of therapy, as further described above.

We do not, however, believe that autologous CAR T therapy will be a viable option in the 1L consolidation setting because of the lengthy lead time for the individualized manufacturing process for autologous CAR T.

Once it is determined that a patient is MRD positive following standard 1L treatment, we believe that the speed at which a patient is treated with CAR T therapy will enhance response rates.

Published results of front-line chemotherapy outcomes suggest that MRD positive patients are likely to progress, and some patients may do so very quickly (i.e., within a matter of weeks after completing 1L therapy).

Furthermore, data suggests that patients who have low burden of disease when they receive CAR T cells tend to have better safety and efficacy outcomes, including lower rates of CRS and more durable remissions.

As a result, we believe that it will be important that patients receive CAR T therapy as soon as possible following an MRD positive diagnosis, which will not allow for the lengthy manufacturing process of autologous CAR T.

Allogeneic T cell products have yet to receive FDA approval though the number of companies developing allogeneic product candidates is substantial.

These include AstraZeneca, plc, Atara Biotherapeutics, Inc., Beam Therapeutics, Inc., Caribou Biosciences, Inc., CRISPR Therapeutics AG, Editas Medicine, Inc., Fate Therapeutics, Inc., Gilead Sciences, Inc., Imugene Ltd., Intellia Therapeutics, Inc., Legend Biotech Corp., Poseida Therapeutics, Inc., Precision Biosciences, Inc., and Sana Biotechnology, Inc.

Some of the allogeneic T cell candidates under development target the same antigens that are part of our clinical pipeline, such as CD19, BCMA and CD70.

Additionally, Cellectis has several fully-owned allogeneic CAR programs that could compete with programs that fall outside our agreement with Cellectis.

Additionally, Cellectis has several fully-owned allogeneic CAR T programs that could compete with programs that fall outside our agreement with Cellectis.

There are also cell therapies under development that are based upon cell types other than the common type of T cells used by us and known as alpha/beta T cells.

These include product candidates derived from natural killer cells, natural killer T cells, gamma/delta T cells and macrophage cells.

Companies developing such therapies include Adicet Bio, Inc., Artiva Biotherapeutics, Inc., Carisma Therapeutics, Inc., Cytovia Therapeutics, Inc., Fortress Biotech, Inc., Celularity, Inc., Century Therapeutics, Inc., Gamida Cell Ltd., Fate Therapeutics, Inc., In8bio, Inc., Kuur Therapeutics Inc., Lyell Immunopharma, Inc., Nkarta, Inc., Shoreline Bio, Inc., and Takeda Pharmaceutical Company Limited.

Companies developing such therapies include Adicet Bio, Inc., Artiva Biotherapeutics, Inc., Carisma Therapeutics, Inc., Cytovia Therapeutics, Inc., Celularity, Inc., Century Therapeutics, Inc., Fate Therapeutics, Inc., Gamida Cell Ltd., In8bio, Inc., Lyell Immunopharma, Inc., Nkarta, Inc., Shoreline Bio, Inc., and Takeda Pharmaceutical Company Limited.

Competition may also arise from non-cell based immune oncology platforms.

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Multiple bi-specific T cell engagers targeting BCMA for myeloma and CD20 for lymphoma are advancing rapidly in development and the first products in each category gained FDA approval in 2022.

Additionally, companies, such as ADC Therapeutics SA, Amgen Inc., Daiichi Sankyo Company, Limited, Gilead Sciences, Inc., GlaxoSmithKline plc, ImmunoGen, Inc., Seattle Genetics, Inc., Silverback Therapeutics, Inc., and Sutro Biopharma, Inc.

Additionally, companies, such as ADC Therapeutics SA, Amgen Inc., Daiichi Sankyo Company, Limited, Gilead Sciences, Inc., GlaxoSmithKline plc, ImmunoGen, Inc., Pfizer Inc., and Sutro Biopharma, Inc.

are pursuing antibody drug conjugates, which utilize the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells.

In addition to the significant competition noted above in oncology markets, as early data in the use of CAR T cell therapy for the treatment of autoimmune disease has been emerging since 2022, there have been many companies initiating autologous and/or allogeneic cell therapy development programs that would be in direct competition to our autoimmune program.

For example, we may experience competition in these markets from companies such as Adicet Bio, Inc., Atara Biotherapeutics, Inc., Autolus Therapeutics plc, BMS, Cabaletta Bio, Inc., Cartesian Therapeutics, Inc., CRISPR Therapeutics AG, Fate Therapeutics, Inc., Gracell Biotechnologies, Inc., ImmPACT Bio USA, Inc., Kyverna Therapeutics, Inc., Nkarta, Inc., Novartis, and Sana Biotechology, Inc.

Many of our competitors, either alone or with their collaboration partners, have significantly greater financial resources and expertise in research and development, pre-clinical testing, clinical trials, manufacturing, and marketing than we do.

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Some preclinical testing may continue even after the IND is submitted.

The IND automatically becomes effective 30 days after receipt by the FDA,

unless the FDA raises concerns or questions regarding the proposed clinical trials and places the trial on a clinical hold within that 30-day time period.

The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the proposed clinical trials and places the trial on a clinical hold within that 30-day time period.

In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.

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

The FDA or the sponsor or its data safety monitoring board may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research patients are being exposed to an unacceptable health risk, including risks inferred from other unrelated immunotherapy trials.

The FDA or the sponsor or its data safety monitoring board may suspend or terminate a clinical trial at any time on various

grounds, including a finding that the research patients are being exposed to an unacceptable health risk, including risks inferred from other unrelated immunotherapy trials.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the biological product has been associated with unexpected serious harm to patients.

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Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data.

If the agency decides not to approve the BLA in its

present form, the FDA will issue a complete response letter that describes all of the specific deficiencies in the BLA identified by the FDA.

If the agency decides not to approve the BLA in its present form, the FDA will issue a complete response letter that describes all of the specific deficiencies in the BLA identified by the FDA.

The deficiencies identified may be minor, for example, requiring labeling changes, or major, for example, requiring additional clinical trials.

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Unique to a fast track product, the FDA may consider for review sections of the BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the BLA, the FDA agrees to accept sections of the BLA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the BLA.

Any product, submitted to the FDA for approval, including a product with a fast track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

A product is eligible for priority review if it has the potential to provide safe and effective therapy where no

satisfactory alternative therapy exists or a significant improvement in the treatment, diagnosis or prevention of a disease compared to marketed products.

Any product submitted to the FDA for approval, including a product with a fast track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated

A product is eligible for priority review if it has the potential to provide safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the treatment, diagnosis or prevention of a disease compared to marketed products.

The FDA will attempt to direct additional resources to the evaluation of an application for a new product designated for priority review in an effort to facilitate the review.

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Fast track designation, priority review, RMAT and Breakthrough therapy designation do not change the standards for approval but may expedite the development or approval process.

We have received RMAT designation for ALLO-715 and ALLO-501A and fast track designation for ALLO-605 and ALLO-316.

We have received RMAT designation for ALLO-715 and cema-cel in r/r multiple myeloma and r/r LBCL, respectively, and fast track designation for cema-cel, ALLO-605, ALLO-316 and ALLO-647.

Post-Approval Requirements

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accordance with an FDA-issued “Written Request” for such a trial.

FDA Approval and Regulation of Medical Devices and Companion Diagnostics

If safe and effective use of a therapeutic depends on an in vitro diagnostic, then the FDA generally will require approval or clearance of that diagnostic, known as a companion diagnostic, at the same time that the FDA approves the therapeutic product.

In August 2014, the FDA issued final guidance clarifying the requirements that apply to approval of therapeutic products and in vitro companion diagnostics.

According to the guidance, if the FDA determines that a companion diagnostic device is essential to the safe and effective use of a novel therapeutic product or indication, the FDA generally will not approve the therapeutic product or new therapeutic product indication if the companion diagnostic device is not approved or cleared for that indication.

Approval or clearance of the companion diagnostic device will ensure that the device has been adequately evaluated and has adequate performance characteristics in the intended population.

The review of in vitro companion diagnostics in conjunction with the review of our product candidates in development for cancer will, therefore, likely involve coordination of review by the FDA’s Center for Drug Evaluation and Research and the FDA’s Center for Devices and Radiological Health Office of In Vitro Diagnostics and Radiological Health.

Under the FDCA, in vitro diagnostics, including companion diagnostics, are regulated as medical devices.

In the U.S., the FDCA and its implementing regulations, and other federal and state statutes and regulations govern, among other

things, medical device design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing, manufacturing, labeling, storage, advertising and promotion, sales and distribution, export and import, and post-market surveillance.

Unless an exemption applies, medical devices, including companion diagnostic tests, require marketing clearance or approval from the FDA prior to commercial distribution.

The two primary types of FDA marketing authorization applicable to a medical device are premarket notification (“510(k) clearance”) and premarket approval (“PMA”).

To obtain 510(k) clearance, a manufacturer must submit to the FDA a premarket notification submission demonstrating that the proposed device is “substantially equivalent” to a legally marketed predicate device.

The FDA’s 510(k) clearance process usually takes from three to twelve months but may take longer.

The FDA may require additional information, including clinical data, to make a determination regarding substantial equivalence.

If the FDA agrees that the device is substantially equivalent to a predicate device currently on the market, it will grant 510(k) clearance to commercially market the device.

If the FDA determines that the device is “not substantially equivalent” to a previously cleared device, the device is automatically designated as a Class III (i.e., high-risk) device.

The device sponsor must then fulfill more rigorous PMA requirements or can request a risk-based classification determination for the device in accordance with the “de novo” process, which is a route to market for novel medical devices that are low to moderate risk and are not substantially equivalent to a predicate device.

After a device receives 510(k) clearance, any modification that could significantly affect its safety or effectiveness, or that would constitute a major change or modification in its intended use, will require a new 510(k) clearance or depending on the modification, approval of a PMA application or de novo classification.

The FDA requires each manufacturer to determine whether the proposed change requires submission of a 510(k), de novo classification or a PMA in the first instance, but the FDA can review any such decision and disagree with a manufacturer’s determination.

If the FDA disagrees with a manufacturer’s determination, the FDA can require the manufacturer to cease marketing and/or request the recall of the modified device until it receives 510(k) clearance, approval of a PMA application, or issuance of a de novo classification.

Also, in these circumstances, the manufacturer may be subject to significant regulatory fines or penalties.

The PMA process, including the gathering of clinical and preclinical data and the submission to and review by the FDA, can take several years or longer.

It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling.

PMA applications are subject to an application fee.

In addition, PMAs for certain devices must generally include the results from extensive preclinical and adequate and well-controlled clinical trials to establish the safety and effectiveness of the device for each indication for which FDA approval is sought.

In particular, for a diagnostic, a PMA application typically requires data regarding analytical and clinical validation studies.

As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the QSR which imposes elaborate testing, control, documentation and other quality assurance requirements.

Approval of a PMA is not guaranteed, and the FDA may ultimately respond to a PMA submission with a not approvable determination based on deficiencies in the application and require additional clinical trial or other data that may be expensive and time-consuming to generate and that can substantially delay approval.

If the FDA’s evaluation of the PMA application is favorable, the FDA typically issues an approvable letter requiring the applicant’s agreement to specific conditions, such as changes in labeling, or specific additional information, such as submission of final labeling, in order to secure final approval of the PMA.

If the FDA’s evaluation of the PMA or manufacturing facilities is not favorable, the FDA will deny approval of the PMA or issue a not approvable letter.

A not approvable letter will outline the deficiencies in the application and, where practical, will identify what is necessary to make the PMA approvable.

The FDA may also determine that additional clinical trials are necessary, in which case the PMA may be delayed for several months or years while the trials are conducted and then the data submitted in an amendment to the PMA.

If the FDA concludes that the applicable criteria have been met, the FDA will issue a PMA for the approved indications, which can be more limited than those originally sought by the applicant.

The PMA can include post-approval conditions that the FDA believes necessary to ensure the safety and effectiveness of the device, including, among other things, restrictions on labeling, promotion, sale and distribution.

Once granted, approval may be withdrawn by the FDA if compliance with post approval requirements, conditions of approval or other regulatory standards are not maintained, or problems are identified following initial marketing.

After a device is placed on the market, it remains subject to significant regulatory requirements.

Medical devices may be marketed only for the uses and indications for which they are cleared or approved.

Device manufacturers must also establish registration and device listings with the FDA.

A medical device manufacturer’s manufacturing processes and those of its suppliers are required to comply with the applicable portions of the QSR, which cover the methods and documentation of the design, testing, production, processes, controls, quality assurance, labeling, packaging and shipping of medical devices.

Domestic facility records and manufacturing processes are subject to periodic unscheduled inspections by the FDA.

The FDA also may inspect foreign facilities that export products to the U.S.

Healthcare Laws and Compliance Requirements

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The federal Anti-Kickback Statute prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering or arranging for the purchase, lease or order of any item, good, facility or service reimbursable under Medicare, Medicaid or other federal healthcare programs.

The term remuneration has been interpreted

broadly to include anything of value.

The term remuneration has been interpreted broadly to include anything of value.

The federal Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, formulary managers, and other individuals and entities on the other.

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HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH) and their implementing regulations, imposes requirements on certain types of individuals and entities relating to the privacy, security and transmission of individually identifiable health information.

Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to business associates that are independent contractors or agents of covered entities that receive or obtain protected health information in connection with providing a service on behalf of a covered entity.

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

HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general

new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

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

Additionally, the federal Physician Payments Sunshine Act within the Affordable Care Act, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) annually report information to CMS related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physicians assistants and nurse

practitioners) and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, physicians and teaching hospitals and certain ownership and investment interests held by physicians and their immediate family members.

In order to distribute products commercially, we must comply with state laws that require the registration of manufacturers and wholesale distributors of drug and biological products in a state, including, in certain states, manufacturers and distributors who ship products into the state even if such manufacturers or distributors have no place of business within the state.

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The downward pressure on health care costs has become very intense.

As a result, increasingly high barriers are being erected to the entry of new products.

increasingly high barriers are being erected to the entry of new products.

In addition, in some countries, cross-border imports from low-priced markets exert a commercial pressure on pricing within a country.

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For example, the Affordable Care Act has substantially changed healthcare financing and delivery by both governmental and private insurers.

Among the Affordable Care Act provisions of importance to the pharmaceutical and biotechnology industries, in addition to those otherwise described above, are the following:

• created an annual, nondeductible fee on any entity that manufactures or imports certain specified branded prescription drugs and biologic agents apportioned among these entities according to their market share in some government healthcare programs;

• increased the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13% of the average manufacturer price for most branded and generic drugs, respectively, and capped the total rebate amount for innovator drugs at 100% of the Average Manufacturer Price (AMP);

• created a new Medicare Part D coverage gap discount program, in which manufacturers must now 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 manufacturers’ outpatient drugs to be covered under Medicare Part D;

• extended manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;

• expanded eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals and added new mandatory eligibility categories for individuals with income at or below 133% of the federal poverty level, thereby potentially increasing manufacturers’ Medicaid rebate liability;

• expanded the entities eligible for discounts under the 340B Drug Discount Program;

• created a Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;

• expanded healthcare fraud and abuse laws, including the Anti-Kickback Statute and the Foreign Corrupt Practices Act (FCPA), created new government investigative powers, and enhanced penalties for noncompliance;

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

• required reporting of certain financial arrangements with physicians and teaching hospitals;

• required annual reporting of certain information regarding drug samples that manufacturers and distributors provide to physicians;

• established a Center for Medicare and Medicaid Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending.

The ACA, among other things, increased the minimum level of Medicaid rebates payable by manufacturers of brand name drugs;

required collection of rebates for drugs paid by Medicaid managed care organizations;

required manufacturers to participate in a coverage gap discount program, under which they must agree to offer point-of-sale discounts (increased to 70 percent, effective as of January 1, 2019) 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;

imposed a non-deductible annual fee on pharmaceutical manufacturers or importers who sell certain “branded prescription drugs” to specified federal government programs, implemented a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted, or injected expanded the types of entities eligible for the 340B drug discount program;

expanded eligibility criteria for Medicaid programs;

created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;

and established a Center for Medicare Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.

There have been legal and political challenges to certain aspects of the Affordable Care Act.

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For example, the Bipartisan Budget Act of 2018 (BBA), among other things, amended the Affordable Care Act, effective January 1, 2019, to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole”.

In December 2018, CMS published a final rule permitting further collections and payments to and from certain Affordable Care Act qualified

health plans and health insurance issuers under the Affordable Care Act risk adjustment program in response to the outcome of federal district court litigation regarding the method CMS uses to determine this risk adjustment.

In December 2018, CMS published a final rule permitting further collections and payments to and from certain Affordable Care Act qualified health plans and health insurance issuers under the Affordable Care Act risk adjustment program in response to the outcome of federal district court litigation regarding the method CMS uses to determine this risk adjustment.

On August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 (IRA) into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in Affordable Care Act marketplaces through plan year 2025.

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For example, in August 2011, President Obama signed into law the Budget Control Act of 2011, which, among other things, created the Joint Select Committee on Deficit Reduction to recommend to Congress proposals in spending reductions.

The Joint Select Committee on Deficit Reduction did not achieve a targeted deficit reduction of at least $1.2 trillion for fiscal years 2012 through 2021, triggering the legislation’s automatic reduction to several government programs.

The Joint Select

Committee on Deficit Reduction did not achieve a targeted deficit reduction of at least $1.2 trillion for fiscal years 2012 through 2021, triggering the legislation’s automatic reduction to several government programs.

This includes aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect beginning on April 1, 2013 and will stay in effect until 2032 unless additional Congressional action is taken.

Under current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 4% in the final fiscal year of this sequester.

Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

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Further, the IRA, among other things (i) directs HHS to negotiate the price of certain high-expenditure, single-source drugs and biologics covered under Medicare and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions will take effect progressively starting in fiscal year 2023, although they may be subject to legal challenges.

Additionally, the Biden administration released an additional executive order on October 14, 2022, directing HHS to report on how the Center for Medicare and Medicaid Innovation can be further leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries.

These provisions will take effect progressively starting in fiscal year 2023.

On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges.

In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act.

On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.

While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework.

Individual states in the United States have also become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

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individual or business from paying, offering, or authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business.

international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

The FCPA also obligates companies whose securities are listed in the United States to comply with accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

Additional Regulation

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If our operations result in contamination of the environment or expose individuals to hazardous substances, we could be liable for damages and governmental fines.

We believe that we are in material compliance with applicable environmental laws and that continued compliance therewith will not have a material adverse effect on our business.

believe that we are in material compliance with applicable environmental laws and that continued compliance therewith will not have a material adverse effect on our business.

We cannot predict, however, how changes in these laws may affect our future operations.

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In addition to regulations in the United States, we will be subject to a variety of regulations in other jurisdictions governing, among other things, clinical trials and any commercial sales and distribution of our products.

Whether or not we obtain FDA approval of a product, we must obtain the requisite approvals from regulatory authorities in foreign countries prior to the commencement of clinical trials or marketing of the product in those countries.

Whether or not we obtain FDA or ex-US approval of a product, we must obtain the requisite approvals from regulatory authorities in foreign countries prior to the commencement of clinical trials or marketing of the product in those countries.

Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application much like the IND prior to the commencement of human clinical trials.

In the EU, for example, a clinical trial application must be submitted to each country’s national health authority and an independent ethics committee, much like the FDA and IRB, respectively.

In the EU, for example, all cell therapy products are considered advanced therapeutic medicinal products (ATMPs) and a clinical trial application must be submitted centrally in accordance with EU clinical trial regulations (CTR) for review by a rapporteur appointed by a member state within the EU region.

In addition, an independent ethics committee is needed in each country, much like the IRB, in the US.

Once the clinical trial application is approved in accordance with a country’s requirements, clinical trial development may proceed.

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If we or our potential collaborators fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

European Union General Data Protection Regulation

In addition to EU regulations related to the approval and commercialization of our products, we may be subject to the EU’s General Data Protection Regulation (EU GDPR).

Privacy Laws and Regulations

In the ordinary course of our business, we may process personal or sensitive data.

Accordingly, we are, or may become, subject to numerous data privacy and security obligations, including federal, state, local, and foreign laws, regulations, guidance, and industry standards related to data privacy, security, and protection.

For example, in addition to EU regulations related to the approval and commercialization of our products, our activities in the EU subject us to the EU’s General Data Protection Regulation (EU GDPR).

The EU GDPR imposes stringent requirements for controllers and processors of personal data of persons in the EU, including, for example, more robust disclosures to individuals and a strengthened individual data rights regime, shortened timelines for data breach notifications, limitations on retention of information, increased requirements pertaining to special categories of data, such as health data, and additional obligations when we contract with third-party processors in connection with the processing of the personal data.

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In addition, the EU GDPR provides that EU member states may make their own further laws and regulations limiting the processing of personal data, including genetic, biometric or health data.

The EU GDPR applies extraterritorially, and we may be subject to the EU GDPR because of our data processing activities that involve the personal data of individuals located in the European Union, such as in connection with our EU clinical trials.

financial year, whichever is higher, private litigation related to processing of personal data brought by classes of data subjects or consumer protection organizations authorized at law to represent their interests, and other administrative penalties.

The EU GDPR applies extraterritorially, and we are subject to the EU GDPR because of our data processing activities that involve the personal data of individuals located in the European Union, such as in connection with our EU clinical trials.

Failure to comply with the requirements of the EU GDPR and the applicable national data protection laws of the EU member states may result in fines of up to €20,000,000 or up to 4% of the total worldwide annual turnover of the preceding financial year, whichever is higher, private litigation related to processing of personal data brought by classes of data subjects or consumer protection organizations authorized at law to represent their interests, and other administrative penalties.

The EU GDPR regulations may impose additional responsibility and liability in relation to the personal data that we process and we may be required to put in place additional mechanisms to ensure compliance with the new data protection rules.

California Consumer Privacy Act

The California Consumer Privacy Act (CCPA) creates new individual privacy rights for consumers (as that word is broadly defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households.

Additionally, numerous US states have passed comprehensive privacy laws.

For example, the California Consumer Privacy Act (CCPA) creates new individual privacy rights for consumers (as that word is broadly defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households.

The CCPA requires covered companies to provide new disclosures to California consumers, affords California residents certain rights related to their personal data, including the right to opt-out of certain sales of personal data, and allows for a new cause of action for certain data breaches.

In addition, the California Privacy Rights Act of 2020 (CPRA), effective January 1, 2023, expands the CCPA.

The CPRA, among other things, gives California residents the ability to limit use of certain sensitive personal data, establishes restrictions on personal data retention, expands the types of data breaches that are subject to the CCPA’s private right of action, and establishes a new California Privacy Protection Agency to implement and enforce the new law.

In addition, the California Privacy Rights Act of 2020 (CPRA), effective January 1, 2023, expanded the CCPA by, among other things, giving California residents the ability to limit use of certain sensitive personal data, establishing restrictions on personal data retention, expanding the types of data breaches that are subject to the CCPA’s private right of action, and establishing a new California Privacy Protection Agency to implement and enforce the CCPA.

As our business progresses, the CCPA and the CPRA may become applicable and impact (possibly significantly) our business activities and exemplifies the vulnerability of our business to the evolving regulatory environment related to personal data and protected health information.

Many other US states—including Virginia, Connecticut, Utah, and Colorado—have passed similar comprehensive privacy laws, and more are likely to do so in the future.

See the section titled “Risk Factors – Risks Related to Our Business and Industry” and “Risk Factors – Risks Related to Government Regulation” for additional information about the laws and regulations to which we may become subject and about the risks to our business associated with such laws and regulations.

Human Capital

As of February 1, 2023, we had 361 total employees, of which 359 are full-time.

As of March 1, 2024, we had 233 total employees, of which 232 are full-time.

Of our full-time employees, 50 hold Ph.D.

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We believe our workforce is key to Allogene’s success and we actively focus on the following core elements of human capital:

(1) our “One Allogene” culture, (2) diversity, equity and inclusion, and (3) recruitment, development and retention.

We have also strived to create a safe working environment and have increased onsite presence since the emergence of COVID-19.

(1) our “One Allogene” culture, (2) diversity, equity, inclusion and belonging, and (3) recruitment, development and retention.

We have also strived to create a safe working environment and have increased onsite presence since the end of the pandemic.

One Allogene Culture

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In addition, our core values of collaboration, leadership, innovation and focus help drive our culture and behaviors and are layered into our performance reviews so that we can keep ourselves and our employees accountable.

Diversity, Equity and Inclusion

We are committed to cultivating, fostering, and preserving a culture of diversity, equity and inclusion (DEI).

Diversity, Equity, Inclusion and Belonging

We are committed to cultivating, fostering, and preserving a culture of diversity, equity, inclusion and belonging (DEIB).

We foster an inclusive environment through respect, collaboration, and open communication.

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We also embrace differences in experience and background, and welcome diversity of opinions and thought when making decisions.

As of February 1, 2023, our employees were self-reportedly 52% women.

As of March 1, 2024, our employees were self-reportedly 51% women.

Of our Director-level and above employees, 47% were self-reportedly women.

In addition, as of February 1, 2023, 67% of all employees were self-reportedly ethnic or racial minorities in the U.S., with 52% Asian, 1% Black or African American, 7% Hispanic or Latino and 7% of other minority groups or two or more races.

In addition, as of March 1, 2024, 67% of all employees were self-reportedly ethnic or racial minorities in the U.S., with 49% Asian, 2% Black or African American, 8% Hispanic or Latino and 8% of other minority groups or two or more races.

Of our Director-level and above employees, 48% were self-reportedly ethnic or racial minorities in the U.S., with 31% Asian, 5% Black or African American, 4% Hispanic or Latino and 8% of other minority groups or two or more races.

Although we are proud of our efforts and metrics to date, we are focused on broadening our outreach and increasing opportunities to underrepresented minorities, including increased recruitment efforts in minority communities by posting our open positions on top job boards for diversity hiring, participating in diversity focused career fairs and hosting science, technology, engineering, and mathematics (STEM)-based outreach in underserved communities at the elementary, junior high and high school level.

We have and will continue to conduct unconscious bias training and provide guidance with respect to best practices with a focus on DEI for interviewers.

Our recruiters and hiring managers are also encouraged to consider candidates from underrepresented groups and to have diverse interview panels.

In addition, we have an Employee Referral Bonus Program that rewards employees for referring candidates from underrepresented groups that are ultimately hired.

Our DEI initiatives are applicable to our practices and policies, such as those on recruitment, compensation and professional development.

We are also progressing the ongoing development of an inclusive work environment that encourages:

Although we are proud of our efforts to attract the best talent from the broadest pool of talent, we continue to focus on broadening our outreach to underrepresented groups by posting our open positions on top job boards to seek diverse, qualified candidates.

We have and will continue to conduct unconscious bias training for interviewers and hiring managers.

Our recruiters and hiring managers have active talent recruitment strategies, including the use of diverse slates.

Our DEIB initiatives are applicable to our practices and policies, such as those on recruitment, compensation and professional development.

We are also progressing the ongoing development of an inclusive work environment grounded in psychological safety that encourages:

• Respectful communication and cooperation between all employees.

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• Teamwork and employee participation, permitting the representation of employee perspectives.

• Employer and employee contributions to the communities we serve to promote a greater understanding and respect for the diversity.

To champion our efforts in this area, we established a governance structure and formed a DEI Committee as well as an associated DEI Advisory Board, each of which is comprised of employees of various levels, departments and backgrounds.

The DEI Committee formalized a DEI mission statement and also advanced a DEI policy that sets forth our commitment to the importance of DEI and the responsibility of our employees to adhere to our policy, including by treating others with dignity and respect at all times.

Pursuant to our DEI policy, all employees are also encouraged to attend and complete annual diversity awareness training to enhance their knowledge to fulfill this responsibility.

The DEI Committee and DEI Advisory Board continually work to identify gaps, respond to feedback provided by peers, and present suggestions on our practices and policies to encourage and enforce an environment in which all employees feel included and empowered to achieve their best.

• Employer and employee contributions to the communities we serve to promote a greater understanding and respect for diversity and inclusion.

To champion our efforts in this area, we established a governance structure and formed a DEIB Committee which is comprised of employees of various levels, departments and backgrounds.

The DEIB Committee formalized a DEIB mission statement and also advanced a DEIB policy that sets forth our commitment to the importance of DEIB and the responsibility of our employees to adhere to our policy, including by treating others with dignity and respect at all times.

Pursuant to our DEIB policy, all employees are also encouraged to attend and complete annual diversity awareness training to enhance their knowledge to fulfill this responsibility.

The DEIB Committee continually works to respond to feedback provided by peers, and present suggestions on our practices and policies to encourage and enforce an environment in which all employees feel included and empowered to achieve their best.

We believe in equal pay for equal work.

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We also regularly review our compensation practices and analyze our compensation decisions for individual employees and our workforce as a whole on at least an annual basis.

In 2020, 2021 and 2022, we conducted a pay equity analysis which we believe demonstrated that our compensation practices and structure are equitable.

If we identify employees with unjustified pay gaps, we review and take appropriate action to ensure fidelity between our stated philosophy and actions.

We plan to continue to seek feedback from the DEI Committee, DEI Advisory Board and all our employees to help us achieve our full potential.

Since 2020, we have conducted a pay equity analysis which we believe demonstrates that our compensation practices and structure are equitable.

We plan to continue to seek feedback from the DEIB Committee, and all our employees to help us achieve our full potential.

Recruitment, Development and Retention

Successful execution of our strategy is dependent on attracting, developing and retaining our employees.

We believe our leadership in the field of allogeneic cell therapy and our culture have allowed us to recruit a talented workforce.

We have and believe we will continue to face significant competition for life science talent.

We believe, however, that our leadership in the field of allogeneic cell therapy and our culture have allowed us to recruit a talented workforce.

In 2023, we recruited over 29 new employees.

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We also actively review employee performance and business needs every six months that lead to promotional opportunities for employees across departments and levels.

While our voluntary attrition rate decreased in 2022 to less than 15%, we believe we will continue to face significant competition for life science talent.

Employee Safety

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What changed 10-K

Item 1. Business