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Item 1. Business

2025-03-11 compared with 2024-02-28 · 327 added, 429 removed, 365 unchanged (67% of the section changed)

We are a clinical-stage cell therapy company advancing a pipeline of product candidates for patients with solid tumors utilizing our proprietary ex vivo genetic and epigenetic T‑cell reprogramming technologies.

Our investigational therapies use the patient’s own cells as the starting point to generate highly tumor-reactive, longer-lasting functional T cells with enhanced ability to defeat solid tumors.

Our innovative reprogramming technologies address what we believe are the primary barriers that limit consistent and long-lasting responses to T‑cell therapy in solid tumors:

T‑cell exhaustion and lack of durable stemness.

Our technologies are designed to generate T cells with the ability to persist and self‑renew while driving durable tumor cytotoxicity, even in the setting of an immunosuppressive tumor microenvironment.

We apply our technologies with the aim of developing T‑cell therapies with improved and durable antitumor responses for patients with solid tumors.

Our technologies can be applied in a target agnostic manner to multiple T‑cell modalities, including chimeric antigen receptor (CAR), tumor-infiltrating lymphocytes (TIL) and T‑cell receptor (TCR) therapies.

Our growing pipeline of promising cell product candidates targets solid tumor indications with large unmet needs that are collectively responsible for approximately 180,000 deaths in the United States annually.

Each of our programs provide opportunities to expand into additional indications beyond the patient populations we are initially targeting.

Our lead product candidates are summarized in Table 1 below:

We are a clinical-stage cell therapy company expecting to enter pivotal trials in 2025 and advancing a pipeline of proprietary next-generation autologous chimeric antigen receptor (CAR) T-cell product candidates for patients with hematologic malignancies and solid tumors.

We are pioneering novel approaches designed to generate T cells that drive long-lasting clinical responses.

The patient’s own living cells are the starting point for our investigational CAR T-cell therapies, and we enhance them with our innovative CAR constructs, technology and manufacturing protocols.

In hematologic malignancies, we are focused on advancing to pivotal trials a product candidate designed to deliver improved outcomes over first-generation CD19 CAR T-cell therapies for patients with B-cell lymphomas.

Our lead program, IMPT-314, currently under evaluation for the treatment of aggressive large B-cell lymphoma, is a dual-targeting CD19/CD20 CAR T-cell product candidate designed to increase complete response rates and prolong the duration of response as compared to the approved CD19‑targeted CAR T-cell therapies.

IMPT-314 is designed with a true ‘OR’ logic gate to target B cells that express either CD19 or CD20 with full potency and is manufactured with a process that enriches for CD62L+ cells to generate more naïve and central memory CAR T cells with enhanced stemlike features and antitumor activity.

To realize the potential of cell therapy for solid tumors, we are also developing next-generation CAR T-cell product candidates enhanced with our anti-exhaustion and additional arming technologies and manufactured with our proprietary protocols.

These approaches are designed to endow CAR T cells with attributes needed to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical responses, including the ability to resist exhaustion, maintain qualities of durable stemness and function in the hostile tumor microenvironment.

In October 2024, we acquired ImmPACT, a privately-owned clinical stage biotechnology company developing next-generation CAR T-cell product candidates, including IMPT-314.

Our pipeline of next-generation CAR T-cell product candidates target cancers with large unmet need and are summarized in Table 1 below:

Lyell’s Pipeline

We were incorporated in June 2018.

Our primary activities to date have included clinical development of T-cell therapies, conducting research and development, acquiring technology, entering into strategic collaboration and license agreements, enabling and executing manufacturing activities in support of our product candidate development efforts, organizing and staffing our company, business planning, establishing our intellectual property portfolio, making regulatory submissions, executing clinical trials, raising capital and providing general and administrative support for these activities.

We are early in our research and development efforts and are in Phase 1 clinical development of LYL797, our ROR1‑targeted CAR T-cell product candidate, and LYL845, our TIL product candidate.

Two additional product candidates that each include novel genetic and epigenetic reprogramming technologies are in preclinical development:

LYL119, a ROR1‑targeted CAR T-cell product candidate and a second generation TIL product candidate.

We do not have any products approved for sale.

Our goal is to realize the potential of cell therapy for solid tumors by developing innovative therapies enhanced with our proprietary T‑cell reprogramming technologies, which in nonclinical studies have been shown to generate potent,

tumor-reactive, long-lasting and functional T cells to drive durable tumor cytotoxicity.

Our goal is to realize the potential of next-generation CAR T-cell therapies for patients with cancer.

We are advancing an innovative CAR T-cell therapy for hematologic malignancies designed to improve outcomes over first‑generation products and are progressing the next wave of innovation of CAR T-cell therapy for solid tumors.

Lyell was founded by leaders in the fields of oncology and cell therapy who have interrogated and elucidated the mechanisms of T‑cell biology and its interactions with cancer for decades.

We believe T‑cell exhaustion and lack of durable stemness, defined as the ability of T cells to self-renew and persist to drive durable tumor cytotoxicity, are primary barriers to effective cell therapy for solid tumors.

Emerging clinical data from the literature has continued to strengthen the rationale for our scientific approach.

To realize the potential of cell therapy for cancer, Lyell utilizes a suite of technologies to endow CAR T cells with attributes needed to drive durable tumor cytotoxicity and achieve

consistent and long-lasting clinical responses, including the ability to resist exhaustion, maintain qualities of durable stemness and function in the hostile tumor microenvironment.

Our product candidates target carefully selected tumor antigens and are enhanced with our proprietary technologies and manufacturing protocols designed to generate potent, tumor-reactive, long-lasting and functional T cells to drive durable tumor cytotoxicity.

Key components of our business strategy to achieve this goal include:

• Efficiently advance our diverse pipeline of product candidates — We believe our autologous T‑cell therapies have the potential to deliver improved, durable clinical outcomes for patients with solid tumors.

We have two wholly‑owned product candidates in two distinct T‑cell modalities, CAR T cell and TIL, currently in Phase 1 development targeting indications with unmet medical needs in large commercial opportunities.

We anticipate having initial clinical data for both programs in 2024 and filing an Investigational New Drug (IND) application for a third wholly-owned product candidate in the first half of 2024.

• Leverage our proprietary, cell reprogramming technology platforms to create highly tumor-reactive, longer‑lasting functional T cells with enhanced ability to defeat solid tumors — We seek to develop T‑cell therapies to defeat solid tumors by addressing the major barriers to effective cell therapy in solid tumors, including overcoming exhaustion of T cells and creating populations of T cells with properties of durable stemness.

Our pipeline of therapeutic candidates includes programs designed to outlast and eradicate solid tumors utilizing our proprietary, stackable and complementary genetic and epigenetic T‑cell reprogramming technologies:

c-Jun overexpression, NR4A3 knockout, Epi‑R TM and Stim‑R TM .

• Continually innovate to develop and advance novel, breakthrough technologies for cell therapy — We are committed to continuing to discover, develop and advance disruptive technologies that may have the potential to revolutionize cell therapy and its promise to improve the lives of patients with solid tumors.

For example, we are advancing a second generation TIL product candidate enhanced with both genetic and epigenetic reprogramming technologies.

In addition, we are advancing our Rejuvenation technology, which is designed to “turn back the clock” to generate more stem-like T cells with reduced epigenetic age and enhanced proliferation ability.

These novel technologies are being advanced with the goal of creating products with even greater benefit to patients with cancer.

• Maintain state‑of‑the‑art infrastructure and expert capabilities to control and innovate cell product manufacturing — We have built and operate a wholly-owned manufacturing facility, LyFE Manufacturing Center™, a multi-product manufacturing center that is producing cell product for our clinical trials.

We have, and will continue to, invest in infrastructure that enables real‑time monitoring of our manufacturing process and the ability to incorporate insights into our research, manufacturing and clinical development efforts.

• Efficiently advance our clinical-stage pipeline of next-generation CAR T-cell product candidates — We believe our autologous T‑cell therapies have the potential to deliver improved, durable clinical outcomes for patients with hematologic malignancies and solid tumors.

Our most advanced wholly‑owned CAR T-cell product candidate, IMPT-314, has the potential to provide meaningfully differentiated benefit in overall and complete response rates and in the duration of the responses over first‑generation CD19 CAR T-cell therapies in patients with relapsed/refractory aggressive large B-cell lymphoma.

IMPT-314 is currently in Phase 1/2 development, and we recently reported positive initial clinical data in patients with aggressive large B-cell lymphoma in the 3 rd line or later (3 rd line+) setting.

We expect to initiate two pivotal clinical programs:

one for patients being treated in the 3 rd line+ setting in mid-2025, and another for patients in the 2 nd line setting by early 2026.

• Advance novel targets and technologies to generate a robust pipeline of next-generation cell therapies designed to deliver durable anti-tumor activity for cancer indications with high unmet medical need and of substantial market size — We are committed to continuing the advancement of disruptive technologies designed to revolutionize cell therapy and its promise to improve the lives of patients with hematologic malignancies and solid tumors.

In addition to developing novel CAR constructs that target undisclosed tumor antigen targets, we are advancing a suite of stackable proprietary technologies to arm T cells to overcome the barriers presented by solid tumors.

Our preclinical programs under development target antigens in solid tumors with high unmet medical need in indications with substantial market size.

We have previously validated our proprietary anti-exhaustion technology and intend to stack newer technologies expressing novel chimeric proteins designed to fully arm our CAR T-cell product candidates to optimize CAR T‑cell killing in the hostile tumor microenvironment and enable durable anti-tumor function in the solid tumor setting.

We anticipate submitting an Investigational New Drug (IND) application for a second CAR T-cell product candidate armed with multiple proprietary technologies and targeting a solid tumor indication in 2026.

• Maintain state‑of‑the‑art infrastructure and expert capabilities to control and innovate cell product manufacturing — We have built and operate a dedicated manufacturing facility, the LyFE Manufacturing Center™ (LyFE), that produces cell product for our clinical trials.

At full capacity, LyFE has the capacity to manufacture more than 1,000 CAR T-cell doses/year and therefore has the capability to support early commercial launch.

We have invested in infrastructure that enables real‑time monitoring of our manufacturing processes and the ability to incorporate insights into our research, manufacturing and clinical development efforts.

Through our recent acquisition of ImmPACT, we acquired the cell manufacturing facility based in Los Angeles that has produced all of the IMPT-314 doses used in clinical trials to date.

As we accelerate development of IMPT-314, we are supplementing our Los Angeles manufacturing capacity through a manufacturing technology transfer to LyFE.

Our manufacturing strategy includes seeking new ways to efficiently, rapidly and cost-effectively scale manufacturing capacity for our cell product candidates for future clinical trials and potential commercialization.

Our proof‑of‑concept technology transfer collaboration for the manufacture of LYL797 using the Cellares Cell Shuttle™ is an example of this.

We are also advancing our Epi-R P2 manufacturing process, which is designed to shorten TIL manufacturing time without impacting cell number and phenotype.

• Generate, secure and defend intellectual property on our differentiated technology platforms and product candidates — We have developed and secured intellectual property, including know-how, through our internal research efforts, licensing agreements and collaborations.

We rigorously analyze, file and protect our intellectual property in an ongoing manner.

• Opportunistically pursue strategic partnerships and collaborations to maximize the potential of our technologies and products – We consider a variety of ways to collaborate with external partners.

Our technologies can be applied in a target and modality agnostic manner to CAR, TIL and TCR therapies to improve the functionality of T cells.

In addition to applying our technologies to advance product candidates in our proprietary pipeline, we also assess opportunities to combine our technologies with targets that other companies are pursuing.

Our product candidates are designed to address large patient populations, and we will evaluate options for partnering programs, indications or geographies with pharmaceutical or biotechnology companies for development and/or commercialization.

• Generate, secure and defend intellectual property on our differentiated technology platforms, CAR constructs and product candidates — We have developed and secured a robust suite of intellectual property, including know-how, through our internal research efforts, licensing agreements and collaborations.

We rigorously analyze, file and protect our intellectual property in various jurisdictions around the world in an ongoing manner.

• Opportunistically pursue strategic opportunities to maximize the potential of our pipeline and capabilities – We consider a variety of ways to collaborate with external partners.

Our technologies can be applied in a target and modality agnostic manner to CAR, tumor infiltrating lymphocyte (TIL) and T-cell receptor (TCR) therapies to improve the functionality of T cells.

We will evaluate options for partnering programs, indications or geographies with pharmaceutical or biotechnology companies for the development and/or commercialization of our product candidates designed to address large patient populations.

We also consider opportunities to acquire or license rights or invest in differentiated product candidates or technologies to complement our pipeline.

Our Reprogramming Technologies

Cell therapy has demonstrated profound results in some patients suffering from hematologic malignancies, but solid tumors are more complex and have evolved multiple mechanisms to evade and ultimately resist clearance by the

immune system.

Our Pipeline Programs

We are advancing a pipeline of next-generation CAR T-cell product candidates, including our lead program, IMPT-314, that is in clinical development for aggressive large B-cell malignancies.

Our preclinical programs target solid

tumor indications.

Each of our programs target cancers with large unmet need with substantial patient populations (see Table 1).

CAR T-cell therapies have demonstrated the curative potential of genetically-engineered autologous cell therapy for cancer.

CARs are synthetic receptors that link an extracellular antigen-binding moiety, usually a single chain variable fragment (scFv) derived from a monoclonal antibody, to intracellular signaling domains.

CARs redirect T-cell functional activity, including cytotoxicity and cytokine secretion, toward cancer cells that share a common target without the limitation of human leukocyte antigen restriction.

A next-generation dual-targeting CD19/CD20 CAR T-cell product candidate designed to increase complete response rates and prolong the duration of responses as compared to the approved CD19‑targeted CAR T-cell therapies for the treatment of large B-cell lymphoma.

Our lead program, IMPT-314, is targeting patients with aggressive relapsed/refractory large B-cell non-Hodgkin lymphoma (NHL).

Lymphoma is a blood cancer that begins in lymphocytes and spreads primarily in lymph nodes, but can also metastasize to the liver, kidney, brain and other organs.

Lymphomas are broadly classified as either Hodgkin or non‑Hodgkin lymphoma, with NHL present in multiple groups of lymph nodes whereas Hodgkin lymphoma is typically located in a single group of lymph nodes, generally in the upper body.

NHL is the more common form of lymphoma, representing approximately 90% of all lymphomas.

The American Cancer Society estimates that more than 80,000 people will be diagnosed with NHL in the United States in 2025 and 545,000 will be diagnosed worldwide.

NHL encompasses a diverse group of blood cancers, with over 90 distinct subtypes, generally classified based on (i) the type of lymphocytes involved (B-cell or T-cell), (ii) the lymphocytes’ phenotype, defined as large cell or small cell and (iii) the disease's rate of progression, which can be characterized as either aggressive or indolent (Figure 1).

We are initially focused on developing IMPT-314 for the treatment of patients with NHL subtypes representing approximately 35% of the over 80,000 patients estimated to be diagnosed with NHL in the United States in 2025 and 545,000 patients worldwide.

The NHL subtypes we intend to initially pursue include diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed follicular lymphoma (tFL) and Grade 3B follicular lymphoma (FL3B).

DLBCL and PMBCL represent approximately 31% and 3% of patients diagnosed with NHL each year, respectively, while tFL and FL3B each represent approximately 1 to 2% of NHL patients diagnosed with follicular lymphoma each year.

We may choose to further expand development to include additional NHL subtypes in the future.

NHL is comprised of over 90 distinct subtypes, of which DLBCL is the most common form accounting for ~31% of all patients diagnosed with NHL.

We are initially focused on developing IMPT-314 for the treatment of patients with NHL subtypes representing approximately 35% of the patients estimated to be diagnosed with NHL.

The NHL subtypes we intend to initially pursue include DLBCL, transformed PMBCL, transformed FL (tFL) and Grade 3B follicular lymphoma (FL3B).

The majority of patients with NHL are successfully treated with frontline combination chemotherapy or targeted agents, but some do not stay in remission for 12 months (relapsed) and others fail to achieve a remission to therapy (refractory).

Aggressive lymphomas such as DLBCL and other large B-cell lymphoma subtypes are more likely to relapse or be refractory to therapy.

Approximately 40% of patients with DLBCL have refractory disease or relapse after their first line of treatment.

Prior to the approval of CD19 CAR T-cell therapies, the prognosis of patients with relapsed/refractory aggressive large B-cell lymphoma was poor, with the then current standard of care resulting in overall response rates of 26% and complete response rates of 7%.

The median overall survival was 6.3 months and only 20% of patients were alive at 2 years.

The three currently approved CD19 CAR T-cell therapies, axicabtagene ciloleucel (axi-cel, YESCARTA ® ), tisagenlecleucel (tisa-cel, KYMRIAH ® ), or lisocabtagene maraleucel (liso-cel, BREYANZI ® ) transformed the treatment landscape by improving overall response rates (72%, 50% and 73%, respectively) with complete response rates (51%, 32% and 54%, respectively) in the 3 rd line+ setting.

While the first generation of CD19 CAR T-cell therapies delivered a major advance in treatment for patients with B-cell lymphoma, there remains a need for therapies that deliver more complete and durable responses.

More than 40% of patients with aggressive large B-cell lymphoma treated in the 3 rd line+ setting with a CD19 CAR T-cell therapy are not disease-free after treatment and 30% of patients do not respond at all.

Of these patients treated with an approved CD19 CAR T-cell therapy, approximately 50% of patients progress or relapse within six months, and the overall survival at one year for patients treated with a CD19 CAR is only 50% to 60%.

IMPT-314 is an autologous dual-targeting CD19/CD20 CAR T-cell therapy designed to kill B cells expressing CD19 and/or CD20 antigens for the treatment of patients with aggressive B-cell malignancies.

We acquired this product candidate through our acquisition of ImmPACT in October 2024.

A dual-targeting, or bispecific, CAR recognizes two targets.

IMPT-314 is rationally designed with a true CD19/CD20 “OR” logic-gated CAR targeting either CD19 or CD20 with full potency, and the cell therapy product is enriched for naive and central memory T cells.

Together, this novel construct and the cell enrichment for naïve and central memory T cells are designed to provide multiple clinical benefits over CD19 CAR T-cell therapies, including:

• Ability to target lower or heterogenous CD19 antigen density and result in a higher percentage of complete responses than with a single targeting CAR agent;

• Increase in duration of responses by preventing relapse due to CD19 antigen escape

• Better cell engraftment, persistence and reduced exhaustion to provide longer duration of responses

IMPT-314 consists of autologous T cells that are genetically modified through transduction with a lentiviral vector expressing a CAR construct composing anti-CD19 and anti-CD20 scFvs in tandem and an intracellular portion that contains the T cell signaling zeta chain (CD3-ζ) and the 4-1BB co-stimulatory domain (Figure 2).

This differentiates IMPT-314 from cell therapies and other therapeutic modalities that singularly target CD19, CD20 or CD22, or bispecific CARs that target two antigens but without full potency as compared to single-targeting CARs.

IMPT-314 contains separate, tandem single-chain variable fragment (scFV) antibody domains designed to target both CD19 and CD20 and is manufactured using a CAR that contains the 4-1BB costimulatory domain and is manufactured with a process to enrich for CD62-positive naïve and central memory T cells.

Antigen heterogeneity, which refers to variation in the expression levels of tumor antigens across cancer cells, can limit the effectiveness of targeted therapies, including CD19 CAR T-cell therapy.

Nonclinical data demonstrated that IMPT-314’s optimized tandem CAR design is capable of killing target cells that express CD19 only, CD20 only or both antigens with full potency, thus it has the potential to achieve a higher percentage of complete responses than a single targeting agent, particularly in those patients with lymphoma who may have a lower or heterogeneous CD19 antigen density.

CD19 antigen escape, a mechanism by which tumor cells evade the host immune system or targeted therapy through loss, downregulation or modification of target antigens, is a known mechanism contributing to disease relapse.

CD20 expression has been shown to be more stable following single-targeted CAR T-cell treatment, as compared to CD19 and CD22.

IMPT-314’s dual-targeting of both CD19 and CD20 was designed to overcome CD19 antigen escape and potentially prolong the duration of responses, as well as to target those malignant B-cells that have limited or no expression of CD19 to achieve a higher overall response rate.

Additionally, IMPT-314 is manufactured to produce a CAR T-cell product with higher proportions of naïve and central memory T cells through a process that enriches for CD62L-expressing cells.

This manufacturing process is

designed to generate CAR T cells with enhanced antitumor activity, which we believe could result in both increased complete response rates and more durable responses.

Naïve T cells are mature T lymphocytes that have differentiated in the bone marrow and undergone central tolerance selection in the thymus, but have not interacted with their antigen.

CAR T cells generated from these CD62L-positive less differentiated T cells have been associated with better engraftment, improved persistence, reduced exhaustion and lower cytokine production compared to CAR T cells generated from traditional processes.

The enrichment of CD62L-expressing T cells does not increase the manufacturing time, which is similar to that of the approved CD19 CAR T-cell therapies.

Data from the ZUMA-7 pivotal trial of axicabtagene ciloleucel in patients with relapsed or refractory large B-cell lymphoma demonstrated an improved overall survival in those patients with a higher median percentage of T cells with a naïve/stem memory phenotype in the administered cell product.

ImmPACT licensed its dual-targeting CD19/CD20 CAR T-cell product candidate from the University of California Los Angeles (UCLA).

Interim Phase 1 data in 13 patients with relapsed/refractory aggressive NHL treated in a UCLA‑sponsored single-center clinical trial were initially published and updated data were presented (Figure 3).

CAR T‑cell naïve patients with relapsed/refractory DLBCL or PMBCL after at least two lines of therapy or MCL, or FL were evaluated.

Autologous T cells were obtained and enriched for CD62L-positive naïve or memory T cells.

Two doses were to be evaluated including 50 and 200 million cells.

Three patients received cell doses below 50 million cells due to manufacturing issues.

The overall response rate was 92% with a complete response rate of 77% (10/13 patients).

The median progression-free survival was 50.1 months, and median overall survival was not reached with a median follow‑up of 32 months (range:

5.7 – not estimable).

The overall survival at three years was 65%.

A favorable safety profile was observed with no cases of cytokine release syndrome (CRS) above Grade 1 and no reported cases of immune effector cell‑associated neurotoxicity syndrome (ICANS).

Two patients in this study who achieved a complete response but experienced disease progression after approximately 18 months and four years respectively were both successfully retreated with the UCLA CD19/CD20 CAR T-cell product and both patients again achieved a complete response.

Interim Phase 1 data in 13 patients with relapsed/refractory aggressive NHL treated with UCLA-314 in a UCLA‑sponsored clinical trial were presented at the 2024 American Association for Cancer Research Special Conference in Cancer Research:

Tumor Immunology and Immunotherapy.

UCLA licensed the CD19/CD20 dual-targeting CAR construct to ImmPACT, who developed a GMP manufacturing process and initiated a Phase 1/2 clinical trial with their product candidate IMPT-314.

We acquired ImmPACT in October 2024 and are continuing the development of IMPT-314.

Phase 1/2 Clinical Trial of IMPT-314

Our ongoing Phase 1/2 trial of IMPT-314 is a multi-center, open-label dose-escalation and dose-expansion clinical trial designed to evaluate the safety and clinical benefit of IMPT-314 and to determine a recommended Phase 2 dose in patients with relapsed/refractory aggressive large B-cell lymphoma.

IMPT-314 has received Fast Track designation from the U.S.

Food and Drug Administration (FDA) for the treatment of relapsed/refractory aggressive large B-cell lymphoma

in the 3 r d line+ setting.

The trial is enrolling patients with relapsed/refractory DLBCL, PMBCL, high-grade B-cell lymphoma (HGBCL), FL3B and tFL.

The trial is enrolling CAR T-cell therapy naïve patients in the 3 rd line+ and 2 nd line settings.

If successful, we may expand into other types of B-cell NHL.

Phase 1/2 Clinical Data

We reported initial data from the ongoing Phase 1/2 trial at the American Society of Hematology 2024 Annual Meeting (ASH).

As of October 22, 2024 (the data cutoff date for the presentation at ASH), 23 patients with relapsed or refractory CAR T-naive large B-cell lymphoma received IMPT-314 and comprised the safety population.

The efficacy evaluable population consisted of 17 patients and was defined as patients with a response assessment at Day 84 or later or an earlier scan with a complete response or progressive disease.

Of the six patients not included in the efficacy evaluable population presented at ASH, two were excluded because they had T-cell histiocyte-rich lymphoma, a histologic subtype with a poor prognosis that is not included in the clinical trial moving forward, and four patients who had not yet reached their Day 84 scan.

The demographic and baseline characteristic data from the patients enrolled into the trial demonstrated a median age of 65 (range, 21 – 87) years, the majority (61%) of patients with DLBCL, and a median of three prior lines of therapy (range, 2 – 6).

Approximately 50% of patients had elevated lactate dehydrogenase levels suggesting high disease burden and 53% of patients received bridging therapy.

The overall response rate for the efficacy evaluable patients was 94% (16/17 patients), with 71% (12/17 patients) achieving a complete response by three months (Table 2 and Figure 4).

At the time the data were presented, three of those four patients were continuing on in the study.

The median follow up was 6.3 months (range 1.2 – 12.5 months) and 71% of patients were experiencing a response when these data were reported.

Best overall response in CAR T-cell therapy naïve patients in the 3 rd line+ cohort in the initial data presented at the 2024 American Society of Hematology annual meeting.

Data cutoff October 22, 2024.

Initial data from the Phase 1/2 trial in patients with relapsed/refractory aggressive large B-cell lymphoma treated with IMPT-314 were presented at American Society of Hematology 2024 Annual Meeting 2024.

The efficacy evaluable population consisted of 17 patients.

The overall response rate was 94% (16/17 patients), with 71% (12/17 patients) achieving a CR by three months.

The median follow up was 6.3 months (range 1.2 – 12.5 months) and 71% of patients were experiencing a response when these data were reported.

In the safety evaluable population of 23 patients, no Grade 3 or greater CRS was reported.

Grade 3 ICANS was reported in 13% (3/23) of patients with a median time to complete ICANS resolution of five days, and rapid improvement to Grade 2 or lower with standard therapy.

Four patients had Grade 3 infections including bacteremia not otherwise specified, tooth infection, urinary tract infection and a herpes zoster infection, all of which responded to treatment and resolved.

Pharmacokinetic data were available from 16 of the efficacy-evaluable patients.

IMPT-314 demonstrated robust expansion and peak cell expansion occurred between Days 7 and 28 after IMPT-314 infusion (median T max = 10 days).

Median peak of expansion (C max ) was 93,723 copies/µg gDNA (range 2,338 – 555,284).

IMPT-314 cells persisted multiple weeks post infusion across multiple patients with median expansion at Day 28 of 11,766 copies/µg gDNA (range 56 – 555,284).

The median peak expansion of IMPT-314 is approximately four‑fold higher than the median peak expansion reported for lisocabtagene maraleucel, a CD19 CAR T-cell therapy approved for patients with relapsed or refractory (R/R) large B-cell lymphoma.

Greater CAR T-cell expansion has been associated with improved treatment response in patients with B-cell lymphoma.

Additionally, the final drug product contained the desired naïve and central memory cell phenotype (median, 91%;

range, 82 – 99%) that has been associated with improved overall survival in other CAR T‑cell clinical studies.

Based on these promising initial and emerging data from the Phase 1/2 IMPT-314 clinical trial and following appropriate regulatory interactions, we intend to initiate a pivotal trial in the 3 rd line+ setting in mid-2025 and a pivotal trial in the 2 nd line setting by early 2026.

Target Markets

We are initially developing IMPT-314 for the treatment of aggressive large B-cell NHL.

NHL is a common blood cancer in the United States and worldwide.

There are more than 60 NHL subtypes that have been identified by the World Health Organization.

Aggressive lymphomas grow and spread quickly and cause more severe symptoms, and these account for approximately 60% of all NHL cases.

B‑cell lymphoma is the most common type of NHL, comprising approximately 85% of all lymphomas in the United States.

We are initially focusing on the subtypes classified as large B-cell lymphomas;

of these diffuse large B-cell lymphoma (DLBCL) is the most common.

Annually, it is estimated that approximately 80,000 people in the United States and 545,000 worldwide will be diagnosed with NHL.

Approximately 200,000 cases of DLBCL are expected to be treated in the U.S., European Union (EU), United Kingdom (UK), China and Japan in 2025, with approximately 24,000 and 13,000 patients receiving treatment in the 2 nd and 3 rd line and later settings, respectively, in the U.S.

and approximately 62,000 and 24,000 patients receiving treatment in the 2 nd and 3 rd line and later settings,

respectively, in the U.S., EU, UK, China and Japan.

Today, the approved CD19 CAR T-cell therapy products have worldwide projected sales of approximately $3 billion and this is expected to nearly double by 2030.

Beyond DLBCL, other subtypes of B-cell NHL that could be evaluated in future trials of IMPT-314 include FL, MZL and MCL, where approximately 200,000, 79,000 and 38,000 patients are expected to be treated in the U.S., EU, UK, China and Japan in 2025.

Our Preclinical Programs

Cell therapy has demonstrated profound results in some patients suffering from hematologic malignancies, but there remains a need for therapies that deliver more complete and durable responses.

Solid tumors are even more complex and have evolved multiple mechanisms to evade and ultimately resist clearance by the immune system.

This has limited the use of cell therapy in solid tumors, which account for 90% of cancer deaths.

Based on clinical data and other scientific evidence, we believe T‑cell exhaustion and lack of durable stemness , which include the ability of T cells to persist and self-renew to drive durable tumor cytotoxicity, are two primary barriers limiting the efficacy of cell therapy in solid tumors.

As illustrated in Figure 1, the highly immunosuppressive solid tumor microenvironment drives T cells down a path of exhaustion as a result of chronic and repeated antigen stimulation in solid tumors, which renders the T cells dysfunctional.

In addition, standard manufacturing processes often generate T‑cell products that are composed of mostly differentiated effector cells – cells that lack the stem-like qualities necessary to enable them to self-renew and sustain therapeutic activity over time.

Cell therapies for solid tumors must overcome two primary barriers:

T-cell exhaustion and lack of durable stemness.

T‑cell exhaustion describes a dysfunctional cellular state characterized by increased expression of cell surface markers such as PD-1, TIM-3 and LAG-3, and, importantly, the functional inability to respond to antigens and eliminate target cells.

A clinical study, previously conducted at the Fred Hutchinson Cancer Center, illustrated the different fates of CAR T cells in solid tumors versus hematologic malignancies and identified T-cell exhaustion as a key barrier to effective cell therapy in the solid tumor microenvironment.

In this study (Riddell et al, Keystone, 2020), autologous ROR1-targeted CAR T cells infused into patients with chronic lymphocytic leukemia underwent rapid expansion and retained T‑cell effector function, leading to tumor cell clearance and clinical responses.

However, when CAR T cells generated with the same method are infused into patients with solid tumors, such as triple-negative breast cancer (TNBC) or non-small cell lung cancer (NSCLC), these T cells often failed to expand adequately, rapidly developed cell surface markers of T‑cell exhaustion and adopted a dysfunctional state.

The outcome of these studies clearly demonstrated that T‑cell exhaustion is a major barrier to effective cell therapy in solid tumors.

Durable stemness describes the quality of a population of T cells to persist through self-renewal, as well as generate differentiated effector cell progenies to provide durable tumor cytotoxicity.

Emerging research has shown that effective immunotherapy requires T‑cell populations with stem‑like characteristics to produce clinical responses, where the presence of stem-like T cells correlates with solid tumor responses to cancer immunotherapy in the setting of solid tumors, including TIL and immune checkpoint blockade therapy (Sade-Feldman et al., Cell , Nov.

Krishna et al., Science , Dec.

We have developed proprietary, stackable and complementary genetic and epigenetic reprogramming technologies designed to address these two major barriers.

Our reprogramming technologies are designed to generate potent T cells with durable cytotoxic function, irrespective of target and irrespective of whether they are delivered as CAR, TIL or TCR therapies.

We have generated T cells that have demonstrated in nonclinical studies the ability to sustain cancer cell killing in murine models of solid tumors and an increased ability to maintain stemness to drive more durable tumor cytotoxicity.

Genetic reprogramming technologies :

Our two proprietary ex vivo genetic reprogramming technologies are c‑Jun overexpression and NR4A3 gene knockout.

c-Jun and NR4A3 are involved in the regulation of the activator protein 1 (AP-1) transcription factor pathway, which plays a key role in T‑cell effector function.

These complementary

reprogramming technologies function within this critical biological pathway to endow T cells with the ability to resist exhaustion.

Overexpression of c-Jun is based on the work of Lyell co-founder, Crystal Mackall, M.D., the Ernest and Amelia Gallo Family Professor of Pediatrics and Medicine at Stanford University and Founding Director of the Stanford Center for Cancer Cell Therapy.

And while there has been recent progress with new cell therapies approved for solid tumors, overall response rates and the duration of response remain low.

To complement our clinical programs, we continue to invest in earlier stage cell therapy research and development utilizing our proprietary technologies.

We expect to submit an IND application in 2026 for a new, armed solid tumor CAR T-cell product candidate with a new target, anti-exhaustion and durable stemness technologies, as well as a new technology designed to overcome the hostile tumor microenvironment.

Our T-cell Enhancement and Manufacturing Technologies

At Lyell, we believe that careful selection and evaluation of our CAR targets is important to ensure we are aiming for larger markets with substantial unmet medical need and to ensure that binding to normal tissues is limited and manageable for safety.

Selecting an appropriate antigen target and designing a potent CAR construct, however, are necessary but insufficient for most solid tumors.

Based on nonclinical evidence and clinical data, we believe there are multiple mechanisms limiting efficacy and durability of cell therapy for solid tumors.

To address this need, we are advancing solid tumor CAR T‑cell product candidates with new CAR targets and that are armed with a suite of proprietary anti-exhaustion and durable stemness technologies, as well as new enhancements designed to overcome the hostile tumor microenvironment.

T-cell exhaustion remains a major barrier for the development of effective CAR T-cell therapy.

We have previously demonstrated Lyell’s proprietary anti-exhaustion technology improves anti-tumor functions in in vitro and in vivo preclinical models.

In patients with triple-negative breast cancer we have shown that our anti-exhaustion technology reduces T-cell exhaustion and improves CAR T-cell pharmacokinetics and tumor infiltration.

Recently, alternative approaches that arm CAR T cells with transforming growth factor beta (TGF-β) blockade or constitutive cytokine signaling to enhance their anti-tumor functionality in the suppressive tumor microenvironment have shown promise in the solid tumor settings.

In addition to developing novel CAR constructs targeting undisclosed tumor antigen targets, our research activities explore stacking these additional approaches to our proprietary anti-exhaustion technology via the expression of novel chimeric protein or polypeptide to optimize CAR T-cell killing in the hostile tumor microenvironment for application in future solid tumor product candidates.

Our technologies and manufacturing approaches designed to generate CAR T cells that can achieve potent and durable anti-tumor cytotoxicity are summarized in Table 3 described below.

Lyell has a suite of technologies designed to enhance the potency and durability of our CAR T-cell product candidates.

Two of our technologies, c-Jun overexpression and our Epi-R manufacturing protocol, have been clinically validated in a Phase 1 study in patients with triple-negative breast cancer, and we are advancing an additional anti‑exhaustion technology, knockout of NR4A3 by gene editing, that has demonstrated even more potent anti-tumor functionality in nonclinical models.

More recently, we have explored new strategies to express novel chimeric proteins to optimize CAR T-cell killing in the hostile tumor microenvironment.

c-Jun Overexpression

Overexpression of c-Jun is based on the work of our co-founder, Crystal Mackall, M.D., the Ernest and Amelia Gallo Family Professor of Pediatrics and Medicine at Stanford University (Stanford) and Founding Director of the Stanford Center for Cancer Cell Therapy.

Mackall discovered that exhausted T cells have an imbalance in the AP‑1 family of transcription factors, and that correcting for this imbalance by overexpression of c-Jun enables T cells to resist exhaustion, infiltrate solid tumors and maintain their functionality and potency.

This work was fully described in a Nature publication in 2019 (Lynn et al., Nature , Dec.

Our second genetic reprogramming technology, NR4A3 gene knockout, builds on the approach of reprogramming of the AP-1 transcription factor pathway to delay exhaustion and improve antitumor function.

This work was fully described in a Nature publication in 2019.

Overexpression of c-Jun was recently validated in a Phase 1 clinical study where a ROR1-targeted CAR T-cell products overexpressing c-Jun demonstrated clinical responses, improved pharmacokinetics, less CAR T-cell exhaustion and CAR T-cell tumor infiltration on histologic examination of on-study tumor biopsies.

These data demonstrated improvement over the clinical data from a prior study conducted at the Fred Hutchinson Cancer Center (Fred Hutch) of a similar ROR-1 CAR T-cell product, but without c-Jun overexpression, in a similar patient population where no responses were observed after a single CAR T-cell treatment and high levels of CAR T-cell exhaustion occurred rapidly.

NR4A3 Gene Knockout

NR4A3 gene knockout builds on the approach of reprogramming of the AP-1 transcription factor pathway to delay exhaustion and improve antitumor function.

We and others have previously observed that the NR4A family of transcription factors is upregulated in exhausted T cells and may contribute to T‑cell exhaustion in part by restricting the activity of AP-1.

We hypothesize that disruption of NR4A3 expression, along with c-Jun overexpression, may further unleash the potential for maximal c-Jun activity and endow greater functional resistance to exhaustion.

Our nonclinical data suggest the combination of these two technologies, NR4A3 gene knockout and c-Jun overexpression, can act in a complementary fashion and may have the potential to further improve the potency and durability of our CAR therapy.

Epigenetic reprogramming technologies:

Our two proprietary ex vivo epigenetic reprogramming technologies are Epi‑R and Stim‑R.

These novel manufacturing technologies generate product candidates with more stem-like cells and with greater potency during ex vivo T‑cell expansion.

Epi-R Manufacturing Protocol

Epi‑R is our proprietary ex vivo manufacturing protocol that is designed to generate populations of stem-like T cells with reduced exhaustion and improved proliferation and antitumor activity.

T cells with properties of durable stemness have an increased ability to self-renew and persist to drive durable tumor cytotoxicity.

This technology is built upon the groundbreaking science conducted at the National Cancer Institute (NCI), where it was demonstrated that products with more stem-like and functional T cells can be achieved by altering the metabolic state of the cells during expansion (Vodnala et al., Science , Mar.

Key NCI scientists conducting this research subsequently joined Lyell where they created the Epi‑R manufacturing protocol, which intentionally produces T‑cell populations with desirable stem-like properties that can be measured both phenotypically and functionally.

Our novel Epi‑R protocol includes proprietary media, well-defined cell activation and expansion processes, as well as customized cytokine combinations.

Epi‑R enables manufacturing of T‑cell therapy product candidates that are highly potent against cancer cells but also retain characteristics of stemness, which have been clinically associated with effective antitumor immunotherapies (Figure 2).

Furthermore, relating specifically to TIL, the application of Epi‑R has generated T‑cell populations that exhibit a high degree of polyclonality, i.e ., the retention of a broad repertoire of TCR clonotypes that may react to a broader set of tumor antigens, thus improving the potential of our TIL therapy to counteract the heterogeneous nature of solid tumors.

Additionally, we are able to reliably and reproducibly manufacture our TIL products from a variety of solid tumors, including those that have been traditionally hard to manufacture such as from checkpoint refractory malignant melanoma, NSCLC and colorectal cancer (CRC).

As shown below, Lyell’s proprietary Epi-R manufacturing protocol produces T-cell populations with long-lived stem-like characteristics.

This protocol is used in our LYL797 CAR T-cell product candidate and in our LYL845 TIL product candidate, which are both in Phase 1 clinical trials, as well as our LYL119 CAR T‑cell product candidate in preclinical development.

Our second epigenetic reprogramming technology, Stim‑R, is a proprietary synthetic-cell mimetic composed of lipid-coated silica micro-rods that mimic the physiological cell-like presentation of signals to control T-cell activation in the manufacturing process.

Current manufacturing platforms typically utilize antibody-conjugated beads that were

developed decades ago for expanding T cells.

T cells with properties of durable

stemness have an increased ability to self-renew and persist to drive durable tumor cytotoxicity.

Lyell developed technology based upon the science conducted at the National Cancer Institute, where it was demonstrated that products with more stem-like and functional T cells can be achieved by altering the metabolic state of the cells during expansion.

CD62L Positive Enrichment

Our lead product candidate, IMPT-314 is manufactured with a process that enriches for CD62L positive cells.

This manufacturing process is designed to generate CAR T cells with enhanced antitumor activity that we believe could result in both increased complete response rates and more durable responses.

Naïve T cells are CD62L positive mature T lymphocytes that have differentiated in the bone marrow and undergone central tolerance selection in the thymus, but have not interacted with their antigen.

CAR T cells generated from these CD62L positive less differentiated T cells have been associated with better engraftment, improved persistence, reduced exhaustion and lower cytokine production compared to CAR T cells generated from traditional processes.

The enrichment of CD62L positive T cells does not increase the manufacturing time, which is similar to that of the approved CD19 CAR T-cell therapies.

Stim-R Technology

Stim‑R is our proprietary synthetic-cell mimetic composed of lipid-coated silica micro-rods that mimic the physiological cell-like presentation of signals to control T-cell activation in the manufacturing process.

Current manufacturing platforms typically utilize antibody-conjugated beads that were developed decades ago for expanding T cells.

This standard approach does not provide precise control over the strength or duration of the signaling that drives T‑cell expansion ex vivo.

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This technology allows for greater control over the duration, intensity and type of signals delivered during cell expansion and manufacturing, resulting in the generation of more potent T‑cell products with desirable phenotypic and functional properties.

T‑cell rejuvenation technologies:

We and others have documented the impact of aging on T‑cell function, which begins to decline after puberty, and at an increasingly accelerated rate after age 65.

Morbidity and mortality from cancer also increase with age.

Thus, we are working to advance another novel reprogramming technology that focuses on rejuvenation of antitumor T cells.

We are developing a method designed to maintain T‑cell identity while reducing the epigenetic age of the cells.

This technology is currently in the research stage.

We have generated data illustrating the ability to “turn back” the epigenetic clock in a process called cellular rejuvenation, without changing the T‑cell’s identity as would occur in the setting of induced pluripotent stem cell-derived T cells.

Our Clinical Programs

We are advancing a diverse pipeline of four wholly-owned product candidates, including two product candidates in Phase 1 clinical development, LYL797 and LYL845.

Two additional product candidates, LYL119 and a second generation TIL product candidate, are in preclinical development.

Each of our programs currently target cancers with large unmet need and provide opportunity to expand into additional indications.

We have deployed our technologies in our pipeline in the following manner to provide rapid clinical proof-of-concept (see Table 1):

• LYL797 incorporates our c-Jun and Epi‑R technologies and is undergoing evaluation in a Phase 1 clinical trial enrolling patients with relapsed/refractory TNBC or NSCLC.

• LYL119 incorporates our c-Jun, NR4A3, Epi‑R and Stim‑R technologies and is currently in preclinical development.

• LYL845 incorporates our Epi‑R technology and is undergoing evaluation in a Phase 1 clinical trial including patients with advanced melanoma, relapsed/refractory NSCLC or CRC.

A genetically and epigenetically reprogrammed ROR1 CAR T‑cell product candidate designed for differentiated potency and durability targeting multiple solid tumor indications.

We are applying our c-Jun and Epi‑R technologies to our lead CAR T‑cell product candidate, LYL797, which is expected to be an intravenously‑administered CAR T‑cell product targeting the receptor tyrosine kinase-like orphan receptor 1 (ROR1) protein.

ROR1 is a fetal protein expressed during embryogenesis and is believed to be important in cell migration, polarity and survival.

It is expressed in several cancer types, including TNBC, NSCLC, ovarian cancer and chronic lymphocytic leukemia, and is generally associated with a poor prognosis.

LYL797 (Figure 3) contains a CAR with a 4-1BB/CD3ζ intracellular domain, a transmembrane domain, an optimized spacer domain and a single-chain variable fragment (scFv) derived from an R12 rabbit monoclonal antibody that recognizes and binds with high specificity to human ROR1.

LYL797 also incorporates c-Jun and a proprietary optimized truncated version of human EGFR (EGFR opt ) used for tracking the CAR T cells in the peripheral blood post treatment and can also be used as a safety measure with the administration of cetuximab, if needed.

LYL797 is manufactured utilizing our proprietary Epi‑R technology.

ROR1 CAR T cell + c-Jun + Epi-R.

Phase 1 Clinical Trial

Our Phase 1 clinical trial (NCT05274451) is designed to evaluate the safety and antitumor activity of LYL797 in patients with ROR1-positive TNBC or NSCLC.

The trial is designed as an open label, dose escalation and expansion trial in patients with relapsed/refractory TNBC who have failed at least two lines of therapy and patients with relapsed/refractory NSCLC who have failed at least one line of therapy.

Per protocol, dose expansion at the recommended dose identified during dose escalation is expected to occur in at least 15 patients with TNBC and 15 patients with NSCLC.

The primary outcome measure assesses the safety and tolerability of LYL797.

Patients will be monitored for cytokine release syndrome (CRS) and immune effector cell‑associated neurotoxicity syndrome, as well as tissue-specific toxicities in ROR1-expressing organs.

Secondary outcome measures include clinical activity based on the evaluation of antitumor activity as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and characterization of the pharmacokinetic profile of LYL797.

Exploratory biomarkers of T‑cell function – exhaustion and stemness – will also be assessed.

In the first half of 2024, we plan to share initial clinical and translational data from the trial from at least 20 patients, which we anticipate will provide an early indication of clinical effect.

Target Indications

We are initially developing LYL797 for the treatment of ROR1-positive TNBC and NSCLC.

Significant subsets of patients with common cancers express ROR1, including TNBC and NSCLC, two of the highest ROR1‑expressing solid tumor indications.

Results from our own ROR1 screening program are consistent with what is reported in the literature.

Using our immunohistochemistry assay in the screening for our Phase 1 trial, as of September 2023, we have found that approximately 50% of patients with TNBC and approximately 33% of patients with NSCLC have tumors that express ROR1.

If successful, we may expand into other ROR1-positive cancers, including potentially ovarian and other solid tumors.

Breast cancer is the second most common cancer in American women.

Currently, the average risk for a woman in the United States to develop breast cancer is approximately 13%.

Breast cancers that demonstrate the absence of estrogen receptor and progesterone receptor and no overexpression of HER2 are referred to as TNBC.

Approximately 10-15% of patients with breast cancer have TNBC and triple negative status tends to be more common in women younger than age 40, who are African American or who have a BRCA1 mutation.

TNBCs have a high tendency to metastasize, and patients are at a higher risk to relapse compared to other molecular types.

TNBCs differ from other types of invasive breast cancer in that TNBC tumors grow and spread faster, have limited treatment options and have a worse prognosis.

In the United States, there are approximately 40,000 new cases of TNBC annually and approximately 22% of breast cancer deaths are from TNBC.

Once TNBC has spread to distant parts of the body, the 5-year survival rate is only 11.5% despite currently available treatment options.

For non-metastatic disease, available treatments include surgery, combined with neoadjuvant and adjuvant chemotherapy.

Chemotherapy is usually anthracycline, alkylator or taxane‑based.

PARP inhibitors, such as

olaparib, may be used in the adjuvant setting.

For metastatic disease, options include combination chemotherapy and pembrolizumab.

At recurrence, patients with tumors that are low HER2 expressing are candidates for Fam-trastuzumab deruxtecan.

Otherwise, the antibody-drug conjugate sacituzumab govitecan-hziy is a treatment option.

Lung cancer is the leading cause of cancer mortality worldwide, accounting for about 2.2 million new cases and 1.8 million deaths worldwide in 2020.

Globally, lung cancer is the leading cause of cancer death for men.

For women, it is the second leading cause of cancer death, following only breast cancer.

In the United States, it is expected to account for approximately 12% of all new cancer cases.

It is estimated that 125,000 deaths from this cancer will occur in the United States in 2024.

NSCLC is more prevalent than small cell lung cancer, constituting approximately 85% of all lung cancer diagnoses.

The 5-year survival rates depend upon the stage of the disease.

NSCLC that is diagnosed at an early stage, typically when the cancer is confined to the lung, has a 5-year survival rate of approximately 65%.

Regional NSCLC, or disease that has spread to nearby lymph nodes or tissues but has not yet metastasized to distant organs, has a 5‑year survival rate of approximately 40%.

Metastatic NSCLC is the most advanced stage of NSCLC where the cancer has spread to distant organs.

The 5-year survival rate for metastatic NSCLC is generally much lower, often less than 10%.

Although there are multiple treatments, including surgery, radiation and approved therapies including chemotherapy, immunotherapy and targeted drug therapy, we believe there remains a tremendous need for better therapies to improve survival.

Nonclinical Data

We have conducted extensive nonclinical in vitro and in vivo studies supporting development of LYL797.

Nonclinical studies of ROR1 CAR T cells that overexpress c-Jun have demonstrated tumor reduction, enhanced cytokine production and tumor infiltration in an aggressive NSCLC syngeneic animal model (Figure 4).

CAR T cells generated with our Epi‑R manufacturing protocol exhibit enhanced durability and cytotoxicity (Figure 5).

Additionally, in a nonclinical xenograft tumor model, LYL797, combining c-Jun overexpression and Epi‑R, demonstrated prolonged survival in a xenograft NSCLC animal model (Figure 6).

Our scientific co-founder, Stanley Riddell, M.D., first tested the hypothesis that overexpression of c-Jun could improve T‑cell function in a rigorous solid tumor model of NSCLC (Figure 4).

Riddell and colleagues utilized a transgenic mouse model with inducible oncogenic driver mutations KRASG12D and p53 deletion.

Once triggered, these mice developed tumors de novo that recapitulate an immunosuppressive tumor microenvironment, akin to human NSCLC.

Previous studies have shown that this aggressive tumor model does not respond to chemotherapy or PD-L1 immunotherapy.

In our study, we observed that this aggressive tumor model is also resistant to treatment with ROR1 CAR T cells, just as was observed in treating human NSCLC with ROR1 CAR T cells.

In contrast, tumor-bearing mice treated with ROR1 CAR T cells that overexpressed c-Jun demonstrated greater infiltration by the T cells into the tumor, enhanced function of those T cells and tumor regression or stabilization in 50% of the mice versus the 100% tumor progression observed in mice treated with ROR1 CAR without overexpression of c-Jun.

Nonclinical efficacy demonstrated with c-Jun overexpressing ROR1 CAR T cells in aggressive NSCLC model.

We have also demonstrated that CAR T cells generated with Epi‑R are able to kill tumor cells over time in an experiment where the CAR T cells are repeatedly challenged to kill tumor cells over multiple rounds (Figure 5).

In this experiment, CAR T cells are co-cultured with ROR1-positive tumor cells, and tumor cell killing can be assessed and quantified by measurement of decreasing fluorescence.

CAR T cells were repeatedly challenged with tumor cells over multiple rounds to assess the durability of tumor cell killing.

Cells generated through standard expansion protocols gradually lose their functionality by the third round and are significantly less effective in killing tumor cells by the fourth round of tumor cell killing.

In contrast, cells generated with the Epi‑R protocol continue to kill tumor cells.

Importantly, the Epi‑R cells are no longer in the Epi‑R protocol, suggesting that the stem-like attribute derived from the epigenetic reprogramming is sustained after the manufacturing protocol and for the duration of the experiment.

The Epi‑R protocol produces populations of T cells with durable cytotoxicity.

In May 2022, at the American Society of Gene and Cell Therapy Annual Meeting, we presented a study that assessed in vivo functional activity of LYL797 (ROR1 CAR T cells with c-Jun and Epi‑R) compared to conventional ROR1 CAR T cells in an established human ROR1-positive H1975 mouse xenograft model.

In this study, LYL797 demonstrated improved expansion in the peripheral blood of tumor-bearing animals and control of tumor growth, which led to prolonged survival (Figure 6).

Taken together, these nonclinical data characterize LYL797 and demonstrate that ROR1-targeted CAR T cells reprogrammed with c-Jun and Epi-R can overcome barriers of T-cell exhaustion and lack of durable stemness.

LYL797 reduces tumor burden and prolongs survival in NSCLC (H1975) xenograft model.

A novel epigenetically reprogrammed TIL product candidate designed for differentiated potency and durability targeting multiple solid tumor indications.

We are applying our epigenetic reprogramming technology, Epi‑R, to develop LYL845, which is expected to be an intravenously‑administered autologous TIL therapy for multiple solid tumors.

Our Epi‑R manufacturing protocol comprises proprietary media, optimized cytokine compositions and well-defined cell activation and expansion protocols used during our manufacturing process.

TIL have previously shown clinical benefit in patients with advanced melanoma and other solid tumors with high mutational burden.

Published data from third-party TIL trials show that treating metastatic melanoma patients with TIL can result in complete and durable responses.

Response rates to TIL therapy in patients with other advanced solid tumors such as lung, colorectal and breast have been much lower than those observed in advanced melanoma.

Broad TIL efficacy has been limited by poor enrichment of tumor-reactive T cells and the poor quality and limited growth potential of expanded T cells.

Failure to maintain polyclonality of TIL during production may also limit their ability to eradicate cancer cells given the inherent heterogeneous nature of solid tumors.

LYL845 incorporates our Epi‑R technology that has shown promising improvements in enhancing T-cell potency, antitumor activity and increased polyclonality of TIL in nonclinical experiments.

We recently received ODD for LYL845 as a potential novel treatment for patients with advanced melanoma.

Phase 1 Clinical Trial

Our Phase 1 clinical trial (NCT05573035) is designed to evaluate the safety and antitumor activity of LYL845 in patients with advanced melanoma, NSCLC and CRC.

If successful, we expect to expand into additional indications.

The trial is designed as an open label, dose escalation and expansion trial in patients with relapsed and/or refractory metastatic or locally advanced solid tumors.

Per protocol, dose expansion at the recommended dose identified during dose escalation is expected to occur in at least 15 patients with advanced melanoma, 15 patients with NSCLC and 15 patients with CRC.

The primary outcome measure assesses the safety and tolerability of LYL845.

Secondary outcome measures include clinical activity based on the evaluation of antitumor activity as evaluated by RECIST criteria and characterization of the pharmacokinetic profile of LYL845.

Evaluation of T-cell expansion, phenotype, clonal diversity and persistence will also be assessed.

Patients will be monitored for CRS.

We plan to share initial clinical and translation data from the trial in the second half of 2024, when we expect to have a meaningful number of patients that can provide an early indication of clinical effect.

Target Indications

We are initially developing LYL845 for advanced melanoma, NSCLC and CRC.

Based on our success with those indications, we plan to include patients with other solid tumors, potentially including head and neck, cervical, breast and pancreatic cancer.

Although patients with these cancers may benefit initially from radiation therapy, chemotherapy,

surgery, and more advanced alternatives such as checkpoint therapies, immunotherapies or targeted therapies, most patients with these types of cancers eventually relapse.

After becoming resistant to initial lines of therapy, patients are limited to palliative care, experimental therapies in clinical trials or chemotherapy regimens that are often highly toxic and largely ineffective.

Overall, despite recent advances in therapeutic development, for most patients diagnosed with advanced solid tumors, long-term survival rates remain low.

Melanoma of the skin is among the most common cancers in the United States behind breast, prostate, lung and CRC.

It is one of the most common cancers in young adults and especially in young women.

It is estimated there are over 100,000 new cases of melanoma diagnosed in the United States per year.

Melanoma arises due to genetic mutations in melanocytes, the pigment producing cells, which can be found in the skin, eye, inner ear and leptomeninges, and represents the most aggressive and the deadliest form of skin cancer.

Although melanoma accounts for only ~1% of all dermatologic cancers, it is responsible for ~80% of deaths from skin cancer.

Only ~16% of patients with advanced melanoma survive for five years.

Available treatment options include surgery, radiation therapy, immunotherapy (PD-1 inhibitors), chemotherapy and targeted therapies (MEK and BRAF inhibitors).

A description of NSCLC can be found above in the section describing the Phase 1 clinical trial for LYL797.

CRC is the second leading cause of cancer-related deaths in the United States.

Most colorectal cancers are a type of tumor called adenocarcinoma, which is cancer of the cells that line the inside tissue of the colon and rectum.

In 2023, an estimated 150,000 people were diagnosed with CRC and approximately 53,000 will die from the disease.

For patients diagnosed with metastatic disease, the 5-year survival rate is approximately 14%.

Approximately 25% of patients have metastatic disease at diagnosis, and about 50% of patients with colorectal cancer will eventually develop metastases.

Over 35% of the patients with a new diagnosis of CRC will die within five years.

Currently available treatments include surgery, radiation therapy, chemotherapy, immunotherapy and targeted therapy (vascular endothelial growth factor, epidermal growth factor receptor, BRAF, NTRK, HER2 and kinase inhibitors) or the antibody-drug conjugate fam‑trastuzumab deruxtecan.

Nonclinical Data

We have conducted nonclinical studies supporting the development of LYL845.

These studies have demonstrated that TIL generated with our Epi‑R technology have phenotypes (stemness markers and cytotoxic T cells) associated with clinical responses in published literature and preserved polyclonal tumor reactive cells.

In addition, manufacturing with Epi‑R allows us to expand TIL from not only immunologically hot tumors such as melanoma, but also immunologically colder tumors such as NSCLC and CRC.

In November 2022, at the Annual Meeting of the Society for Immunotherapy of Cancer (SITC), we presented data that demonstrated the ability of our Epi‑R technology to yield a product (LYL845) with qualities that have been linked with antitumor functionality and improved outcomes in previous TIL clinical trials, including a greater proportion of CD8+ cytotoxic T cells and enrichment of T cells with stem-like profiles (Figure 7), and better metabolic fitness compared to control TIL.

LYL845 is enriched for cells with characteristics associated with improved clinical outcomes (Krishna et al., Science, Dec.

We also presented at the 2022 meeting of SITC comprehensive analyses of transcriptomic profiles, polyclonality and prediction of tumor reactive T cell clones in our LYL845 product candidate.

In particular, our bioinformatic analyses demonstrated that LYL845 products expanded using Epi‑R manufacturing protocol at clinical scale were highly polyclonal and preserved approximately 94% of the predicted tumor reactive clones (Figure 8).

Further, preserved putative tumor reactive clones in LYL845 products have increased stemness and reduced exhaustion-associated genes compared to TIL products derived from the standard process.

The tumor-specific reactivity of LYL845 was confirmed by demonstrating dose-dependent antitumor cytolytic activity and cytokine secretion in tumor cell specific co-culture assays.

LYL845 TIL preserve ~94% of predicted tumor reactive clones to enable targeting of heterogeneous solid tumors.

We have also shown in nonclinical studies with TIL products generated from tissue from five donors using either the LYL845 process or standard process that TIL products generated with our LYL845 Epi-R manufacturing protocol express more genes associated with stem-like phenotypes such as TCF-7 and SELL versus TIL products generated with the standard process which express more genes associated with exhaustion such as TIGIT and PD-1 (Figure 9).

Transcriptomic data of TIL products generated from five donor tissues using either standard or LYL845 Epi-R manufacturing protocol (four melanoma and one NSCLC) demonstrate that LYL845 generated with Epi-R are enriched for T cells with stem-like quality.

An innovative ROR1 CAR T-cell product candidate designed for enhanced cytotoxicity.

A key pillar of our strategy is to continually innovate to develop and advance novel, breakthrough technologies that address key barriers to effective cell therapy for solid tumors.

We have advanced a new genetic reprogramming technology, NR4A3 knockout, and a new epigenetic reprogramming technology, Stim‑R, that are being applied in our new CAR T-cell product candidate, LYL119 (Figure 10).

These technologies are stackable and complementary to c-Jun and Epi‑R and are designed to further improve the antitumor potency and durability of T cells.

ROR1 CAR T cell + c-Jun + NR4A3 KO + Epi-R + Stim-R.

LYL119 is being advanced with the goal of potentially creating even greater benefit for patients with ROR1-positive solid tumors.

An IND application is expected to be submitted for LYL119 in the first half of 2024.

c-Jun is a transcription factor in the activator protein 1 (AP-1) pathway, which plays a key role in driving T‑cell function.

NR4A family transcription factors contribute to T-cell exhaustion by restraining AP‑1 activity.

Reducing NR4A

expression enhances T-cell function associated with increased expression of AP‑1‑regulated genes.

Our NR4A3 knockout reprogramming technology furthers the hypothesis that reprogramming of the AP-1 transcription factor pathway in T cells may delay exhaustion and improve anti-tumor function.

Our Stim-R technology is a customizable, degradable, synthetic cell biomimetic composed of lipid-coated silica micro-rods that mimic the physiological cell-like presentation of signals to control T-cell properties.

Stim-R allows for rapid tuning of T-cell signal presentation to generate T-cell products with desirable phenotypic and functional properties.

We have optimized a Stim-R formulation to control T-cell stimulation and expansion to generate T-cell products with an enhanced activation state, resulting in improved potency compared with conventional T-cell activating reagents.

In nonclinical models, we have shown that Stim-R CAR T cells demonstrate prolonged persistence and enhanced cytotoxicity in response to serial antigen stimulation.

Nonclinical Data

In November at the 2023 meeting of SITC, we presented nonclinical data demonstrating that LYL119 enhances survival in vivo in a murine H1975 xenograft tumor model, even at a very low CAR T‑cell dose of 100,000 CAR T cells (Figure 11).

Additionally, both in vitro and in vivo nonclinical data demonstrated that the combination of all four of our genetic and epigenetic reprogramming technologies resulted in superior cytotoxicity, improved proliferation and sustained cytokine production upon repeated antigen stimulation compared to various controls lacking one or more of the reprogramming technologies.

LYL119 eliminated H1975 (NSCLC) xenograft tumors and improved survival, even at low doses.

Nonclinical data demonstrate that CAR T cells enhanced with four technologies (c-Jun overexpression, NR4A3 knockout and manufactured with Epi-R and Stim-R) mediated anti-tumor response and enhanced survival in a murine xenograft tumor model, even at a very low CAR T‑cell dose of 100,000 CAR T cells.

Additionally, both in vitro and in vivo nonclinical data demonstrated that the combination of all four of these technologies resulted in superior cytotoxicity, improved proliferation and sustained cytokine production upon repeated antigen stimulation compared to various controls lacking one or more of the reprogramming technologies.

Undisclosed New Technologies

Recently, alternative approaches that arm CAR-T cells with TGF-β blockade or constitutive cytokine signaling to enhance their anti-tumor functionality in the suppressive tumor microenvironment have shown promise in the solid tumor settings.

In addition to developing novel CAR constructs that target undisclosed tumor antigen targets, our research activities explore stacking our proprietary anti-exhaustion technology and these additional approaches targeting the tumor microenvironment via the expression of novel chimeric proteins or polypeptides (Table 3) to optimize more durable CAR T-cell killing for application in future solid tumor product candidates.

Our Manufacturing Capabilities

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Our LyFE Manufacturing Center™ located in Bothell, Washington is approximately 73,000 square feet and is comprised of manufacturing suites, laboratories and offices.

Our LyFE Manufacturing Center was commissioned and designed to be in compliance with U.S.

and European Union current Good Manufacturing Practices (cGMP) standards and has a flexible and modular design enabling CAR T-cell, TIL, TCR T-cell and cGMP viral vector production to control and de-risk the manufacturing sequence and timing of the major components of our supply chain.

At full staffing and capacity, we expect to be able to manufacture >1,000 patient CAR T‑cell products/year, able to support our clinical development needs for IMPT-314 and other pipeline programs, as well as early commercial launch if IMPT-314 is approved.

LyFE was commissioned and designed to be in compliance with U.S.

and EU current Good Manufacturing Practices (cGMP) standards and has a flexible and modular design enabling CAR T‑cell, TIL, TCR T-cell therapies and cGMP viral vector production to control and de-risk the manufacturing sequence and timing of the major components of our supply chain.

Owning our own facility has enabled seamless collaboration across research, process development and manufacturing for high-quality reproducibility at manufacturing scale.

We are currently producing clinical supply for our Phase 1 trials at our LyFE Manufacturing Center.

At full staffing and capacity, we expect to be able to manufacture approximately 500 infusions per year depending on product candidate mix.

While we believe this capacity is sufficient to support our pipeline programs into pivotal trials and, if approved, early commercialization, we are also advancing multiple strategic alternatives to innovate and scale manufacturing in the future.

We are evaluating third-party manufacturing options, such as the recently initiated CAR T-cell proof-of-concept collaboration with Cellares, as part of an overall CAR T‑cell manufacturing strategy to build scale and reduce cost.

For TIL, we are advancing our Epi-R P2 manufacturing protocol to shorten delivery time of TIL product to patients.

In November 2023 at SITC, we presented nonclinical data demonstrating that our Epi-R P2 TIL manufacturing process reduces the TIL culture duration to less than three weeks (from the standard time of four to six weeks) while maintaining the desired yield, stemness phenotype and retention of tumor reactive clones.

Clinical supply for our Phase 1/2 trial of IMPT-314 is currently manufactured in our manufacturing facility in Los Angeles, California, that we acquired in connection with the acquisition of ImmPACT.

As we accelerate development of IMPT-314, we are supplementing our Los Angeles manufacturing capacity through a manufacturing technology transfer to LyFE.

We are focused on maintaining a manufacturing strategy that is operationally efficient to maximize our capacity and avoid any disruption to clinical trial supply.

The pharmaceutical industry is highly competitive and dynamic, owing to rapidly advancing technologies.

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Any product candidates that we successfully develop and commercialize will compete with existing treatments and new treatments that may become available in the future.

In addition, during development, our product candidates may compete against other experimental treatments, whether cell therapy or other modalities, for patients with certain histologies or patients with tumors expressing certain antigen targets of interest.

We are aware of a number of companies using ex vivo cell therapy approaches to treat solid tumors.

Some of these companies may have substantially greater financial and other resources than we have, such as larger research and development staff and well-established marketing and sales forces, or may operate in jurisdictions where lower standards of evidence are required to bring products to market.

T‑cell therapies for the treatment of solid tumors are being developed by a number of companies, including but not limited to Arcellx, Inc., AstraZeneca plc, Autolus Therapeutics plc, Bristol Myers Squibb Co., Gilead Sciences Inc., Immunocore Holdings plc, Iovance Biotherapeutics Inc., the Janssen Pharmaceutical Companies of Johnson & Johnson, Nanjing Legend Biotech and Novartis AG.

On February 16, 2024, the FDA approved the first TIL therapy, Iovance’s lifileucel, for the treatment of unresectable or metastatic melanoma.

We are also aware that other companies are developing therapies in modalities such as monoclonal antibodies and antibody drug conjugates for cancers that express ROR1, such as Boehringer Ingelheim International GmbH, CStone Pharmaceuticals and Merck & Co., Inc.

Among companies developing cell therapies for solid tumors, we believe we are substantially differentiated by our reprogramming technologies, knowledge, experience, scientific personnel and robust intellectual property portfolio.

We believe there are many factors affecting the success of any of our product candidates, including efficacy, safety, accessibility, price and cost of manufacturing.

License, Collaboration and Success Payment Agreements

Fred Hutch License Agreement and Success Payment Agreement

In December 2018, we entered into a license agreement with Fred Hutchinson Cancer Center (Fred Hutch) (as amended in June 2019, September 2019, January 2020, and August 2020) that grants us a worldwide, sublicensable license under certain patent rights (exclusive) and certain technology (non-exclusive), to research, develop and commercialize products and processes for all fields of use utilizing CARs and/or TCRs.

We paid Fred Hutch an upfront payment of $150,000.

In connection with the license agreement, we entered into a letter agreement with Fred Hutch pursuant to which we issued to Fred Hutch 1,075,000 shares of our common stock.

The license agreement will expire, on a product-by-product and country-by-country basis, on the later of (a) the expiration of the last to expire valid claim of the patents rights covering such product in such country and (b) ten (10) years after the date of the first commercial sale of such product in such country.

We may terminate the agreement at will in its entirety or with respect to any patent.

Fred Hutch has the right to terminate the agreement in the event of our uncured breach.

We also entered into a letter agreement with Fred Hutch in December 2018 under which we agreed to make success payments to Fred Hutch, payable in cash or publicly tradable equity at our discretion.

These success payments are based on increases in the per share fair market value of our common stock (as all our Series A convertible preferred stock were converted into an equivalent number of shares of our common stock upon the closing of our initial public offering in 2021) during the success payment period, which is a period of time that begins on the date of our letter agreement with Fred Hutch and ends on the earlier of:

(a) the ninth anniversary of that date and (b) the earlier of (i) the date on which we

sell, lease, transfer or exclusively license all or substantially all of our assets to another company and (ii) the date on which we merge or consolidate with or into another entity (other than a merger in which our pre-merger stockholders own a majority of the shares of the surviving entity).

Success payments will be owed (if applicable) after measurement of the value of our common stock in connection with the following valuation dates during the success payment period:

(1) the date of the first anniversary of our initial public offering;

(2) the second anniversary of such date;

(3) each two year anniversary thereafter (i.e., the four year anniversary, six year anniversary, etc.

of such date);

(4) the date on which we sell, lease, transfer or exclusively license all or substantially all of our assets to another company;

(5) the date on which we merge or consolidate with or into another entity (other than a merger in which our pre-merger stockholders own a majority of the shares of the surviving entity);

and (6) the last day of the nine-year period.

Any success payment will generally be made within 45 days after the applicable valuation date, except that in the case of a merger or sale of all of our company’s assets, the success payment will be made on the earlier of the 90 th day following the transaction or the first date that transaction proceeds are paid to any of our stockholders.

In the case of (1), (2) and (3), the value of our common stock will be determined by the average trading price of a share of our common stock over the consecutive 90-day period preceding the date the success payment is made;

the value will otherwise be determined either, in the case of a merger or stock sale, by the consideration paid in the transaction for each share of our stock or the stock of the acquiring entity (or their parent or affiliate).

The amount of a success payment is determined based on whether the value of our common stock meets or exceeds certain specified threshold values ascending from $18.29 per share to $91.44 per share, in each case subject to adjustment for any stock dividend, stock split, combination of shares or other similar events.

Each threshold is associated with a success payment, ascending from $10.0 million at $18.29 per share to a cumulative total of $200.0 million at $91.44 per share, payable if such threshold is reached.

Any previous success payments made to Fred Hutch are credited against the success payment owed as of any valuation date, so that Fred Hutch does not receive multiple success payments in connection with the same threshold.

The success payments paid to Fred Hutch will not exceed, in aggregate, $200.0 million, which would be owed only when the value of the common stock reaches $91.44 per share.

To date, no success payments have been incurred as the per share fair value of our common stock was below the price required for payment.

Stanford License Agreement and Success Payment Agreement

In January 2019, we entered into a license agreement with The Board of Trustees of the Leland Stanford Junior University (Stanford) that grants us a worldwide, sublicensable license under certain patent rights (exclusive), and certain other patent rights and technology (non-exclusive), to research, develop and commercialize products and processes for all fields of use utilizing CARs and/or TCRs.

We also have the right to add certain Stanford patent applications covering certain inventions that are improvements to the existing patents and patent applications, as well as a right of first negotiation for other patent applications covering inventions made in the principal investigator’s lab that relate to and are necessary or useful for utilizing CARs and/or TCRs.

We paid Stanford an upfront payment of $400,000.

In connection with the license agreement, we entered into a letter agreement in January 2019 with Stanford pursuant to which we issued to Stanford 910,000 shares of our common stock.

We are required to pay Stanford an annual maintenance fee in the mid tens of thousands of dollars on the second anniversary of entering into this agreement, and each anniversary thereafter until the date of the first commercial sale of a licensed product.

We are obligated to pay Stanford up to a maximum of $3.7 million per target upon achievement of certain specified clinical and regulatory milestones.

We are also obligated to pay Stanford $2.5 million collectively for all licensed products upon our achievement of a certain commercial milestone.

In addition, the license agreement provides that we are required to pay Stanford low single-digit tiered royalties based on annual net sales of the licensed products by us and by our sublicensees.

If we seek to challenge the validity of any of the licensed patents, during the pendency of such action our royalty rate will increase, and if the outcome of such challenge finds that patent is both valid and infringed our royalty rate will increase further.

We are also required to pay Stanford (a) royalties in the mid-teens percentage of the payments that we receive from sublicensees of the rights solely licensed to us by Stanford, or (b) sublicensing fees if sublicensed with other intellectual property on a tiered basis up to $300,000.

The license agreement will expire, on a licensed product-by-licensed product and country-by-country basis, on the expiration of the last to expire valid claim of the licensed patents rights covering such licensed product in such country.

We may terminate the agreement at will in its entirety or with respect to any licensed patent.

Stanford has the right to terminate the agreement in the event of our uncured breach.

We also entered into a letter agreement with Stanford in October 2020, under which we agreed to make success payments to Stanford, payable in cash or publicly tradable equity at our discretion.

during the success payment period, which is a period of time that begins on the date of our letter agreement with Stanford and ends on the earlier of:

(a) the ninth anniversary of that date and (b) the earlier of (i) the date on which we sell, lease, transfer or exclusively license all or substantially all of our assets to another company and (ii) the date on which we merge or consolidate with or into another entity (other than a merger in which our pre-merger stockholders own a majority of the shares of the surviving entity).

Success payments will be owed (if applicable) after measurement of the value of our common stock in connection with the following valuation dates during the success payment period:

(1) the date of the first anniversary of our initial public offering;

(2) the second anniversary of such date;

(3) each two year anniversary thereafter (i.e., the four year anniversary, six year anniversary, etc.

of such date);

(4) the date on which we sell, lease, transfer or exclusively license all or substantially all of our assets to another company;

(5) the date on which we merge or consolidate with or into another entity (other than a merger in which our pre-merger stockholders own a majority of the shares of the surviving entity);

and (6) the last day of the nine-year period.

Any previous success payments made to Stanford are credited against the success payment owed as of any valuation date, so that Stanford does not receive multiple success payments in connection with the same threshold.

The success payments paid to Stanford will not exceed, in aggregate, $200.0 million, which would be owed only when the value of the common stock reaches $91.44 per share.

To date, no success payments have been incurred as the per share fair value of our common stock was below the price required for payment.

GSK Collaboration and License Agreement

In 2019, we entered into a collaboration and license agreement with GlaxoSmithKline (GSK) that became effective on July 7, 2019 and was amended in June 2020 and December 2021 (GSK Agreement) for potential T‑cell therapies that apply our platform technologies and cell therapy innovations with TCRs or CARs under distinct collaboration programs.

The GSK Agreement defined two initial collaboration targets, CD19 and NY-ESO-1, and allowed GSK to nominate seven additional targets through July 2024.

After agreeing on the programs for those targets, we were expected to perform research and development services for each agreed program up until a defined point (GSK Option Point), at which time GSK would decide whether or not to exercise an option to obtain a license from us (License Option) and take over the future development and commercialization.

For the LYL331 program (NY-ESO-1 TCR with c-Jun), GSK exercised the License Option in April 2021 and assumed sole responsibility for future development and commercialization of the program at its own cost and expense.

No IND for LYL331 was submitted to the FDA.

For the LYL132 program (NY-ESO-1 TCR with Epi‑R), we filed an IND application, which cleared in January 2022, though no patients were treated.

The program targeting CD19 was a research effort.

No additional targets were nominated over the term of the GSK Agreement.

GSK terminated the GSK Agreement effective December 24, 2022 and Lyell has discontinued any further work on these programs.

We received a non-refundable upfront payment of $45.0 million under the GSK Agreement.

In connection with the GSK Agreement, in May 2019, we also entered into a stock purchase agreement with GSK (GSK Stock Purchase Agreement), pursuant to which we agreed to sell 30,253,189 shares of Series AA convertible preferred stock at a price of $6.78 per share, which was above the issuance date estimated fair value of $4.84 per share.

The difference between the per share values resulted in $58.6 million additional deemed consideration, bringing the total upfront payment of the GSK Agreement to $103.6 million.

In addition, during development and clinical trials, our product candidates may compete against other experimental treatments, whether cell therapy or other modalities, for patients with certain histologies or patients with tumors expressing certain antigen targets of interest.

If approved, our product IMPT-314 will need to compete against other products approved in the 2 nd and 3 rd line+ settings in our approved indications, including any approved CD19 CAR T‑cell therapies, monoclonal antibodies targeting CD19, antibody-drug conjugates, selective inhibitors of exportin 1 and bispecific antibodies.

We are also aware of a number of companies using autologous or allogeneic CAR T-cell therapy approaches to treat hematologic malignancies and solid tumors.

Some of these companies have substantially greater financial and other resources than we have, such as larger research and development staff and well-established marketing and sales forces, or operate in jurisdictions where we do not have staffing or resources.

CAR T‑cell therapies for the treatment of hematologic malignancies and solid tumors are being developed by a number of companies, including but not limited to Arcellx, Inc., Allogene Therapeutics, Inc., Arsenal Biosciences, Inc., AstraZeneca plc, Autolus Therapeutics plc, Bristol Myers Squibb Co., Caribou Biosciences, Inc., Cargo Therapeutics, Inc., Gilead Sciences Inc., Immunocore Holdings plc, Johnson & Johnson, Nanjing Legend Biotech, Novartis AG and Poseida/F.

Hoffmann-La Roche AG .

We are also aware that other companies are developing therapies in modalities such as bispecific antibodies for B-cell lymphomas, including AstraZeneca, F.

Hoffmann-La Roche AG and Amgen Inc.

Among companies developing CAR T-cell therapies for hematologic malignancies and solid tumors, we believe we are substantially differentiated by our technologies, manufacturing protocols and capabilities, knowledge, experience, scientific personnel and robust intellectual property portfolio.

We believe there are many factors affecting the success of any of our product candidates, including efficacy, safety, accessibility, price and scale and cost of manufacturing.

License and Collaboration Agreements

UCLA License Agreement

As a result of our acquisition of ImmPACT, we assumed its rights and obligations under a license agreement with the Regents of the University of California, acting through The Technology Development Group of UCLA, dated February 18, 2021, as amended (the UCLA License Agreement).

Pursuant to the UCLA License Agreement, UCLA granted us an

exclusive, royalty‑bearing license, with the right to sublicense through a specified number of tiers, under certain patent rights owned by UCLA and certain patent rights co‑owned by UCLA and the Seattle Children’s Hospital doing business as the Seattle Children’s Research Institute (SCRI) and a non‑exclusive, royalty‑bearing license, with the right to sublicense through a specified number of tiers, under related technical information, in each case related to our CD19/CD20 program, for the development, use and sale of products or services associated with certain inventions made in the course of research by UCLA and SCRI in all fields of use.

In accordance with the Patent and Trademark Law Amendments Act (the Bayh‑Dole Act), UCLA granted the U.S.

federal government a non‑exclusive, non‑transferable, irrevocable, paid‑up license to the licensed patents.

Under the UCLA License Agreement, we are obligated to diligently develop and commercialize licensed products and to achieve certain development, regulatory and commercialization diligence milestones.

If, subject to our right to extend such diligence milestones in certain circumstances, we are unable to meet our diligence obligations and do not agree with UCLA to modify such obligations, UCLA has the right and option to either terminate the license agreement or convert the granted rights to a non‑exclusive license.

We are also required, subject to certain exceptions, to provide UCLA with an affordable access plan within a specified time following the first commercial sale of a licensed product that is intended to support affordable access to licensed products in certain low‑ and middle‑income countries and other countries in which we do not intend to commercialize licensed products.

UCLA and SCRI reserved, for themselves and for other nonprofit and academic research institutions, their rights to use the patent rights and technical information licensed to us for education and research purposes and to publish results arising therefrom, and for UCLA to offer and perform clinical diagnostic and prognostic services for patients in the University of California healthcare system, in each case subject to certain exclusions.

Our rights under the UCLA License Agreement are also subject to certain government rights.

Under the UCLA License Agreement, ImmPACT paid UCLA a small upfront license issue fee and, upon our assumption of the agreement in connection with our acquisition of ImmPACT, we are obligated to pay a nominal, tiered annual license maintenance fee each year of the term until we make the first commercial sale of a licensed product.

Upon the achievement of specified development, regulatory and commercial milestones, we are obligated to pay UCLA one-time milestone payments of up to an aggregate amount in the mid-single digit millions for each commercialized licensed product.

In addition, we are obligated to pay UCLA a tiered royalty on worldwide annual net sales of any commercialized licensed products in the low‑ to mid-single digits percentage, subject to specified and capped reductions and a tiered minimum annual royalty payment of between a low-five figure and a low-six figure amount.

ImmPACT reimbursed UCLA for all patent costs incurred prior to the effective date of the UCLA License Agreement, and we are obligated to reimburse UCLA for all patent costs incurred by them during the term of the license agreement.

The license agreement will expire, on a product-by-product and country-by-country basis, on the later of (a) the expiration of the last to expire valid claim of the patent rights covering such product in such country and (b) ten (10) years after the date of the first commercial sale of such product in such country.

UCLA has the right to terminate the agreement in the event of our uncured material breach, subject to a specified notice and cure period, or upon certain insolvency events.

We may terminate the agreement for convenience, subject to a specified notice period.

Intellectual Property

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Our policy is to seek to protect our proprietary position by, among other methods, filing patent applications in the United States and in jurisdictions outside of the United States related to our proprietary technology, inventions, improvements and product candidates that are important to the development and implementation of our business.

We also rely on trade secrets and know-how relating to our proprietary technology and product candidates, continuing innovation and in-licensing opportunities to develop, strengthen and maintain our

proprietary position in the field of cell and gene therapy.

We additionally plan to rely on data exclusivity, market exclusivity and patent term extensions, when available, and, as appropriate, have sought and in the future may seek again and rely on regulatory protection afforded through ODDs.

We also rely on trade secrets and know-how relating to our proprietary technology and product candidates, continuing innovation and in-licensing opportunities to develop, strengthen and maintain our proprietary position in the field of cell and gene therapy.

We additionally plan to rely on data exclusivity, market exclusivity and patent‑term extensions, when available, and, as appropriate, have sought and in the future may seek again and rely on regulatory protection afforded through Orphan Drug designations.

Our commercial success may depend in part on our ability to obtain and maintain patent and other proprietary protection for our technology, inventions and improvements;

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and to operate without infringing on the valid and enforceable patents and other proprietary rights of third parties.

We have in-licensed and procured, and filed for numerous patent applications, which include claims directed to compositions, methods of use, processes, dosing and formulations, and possess substantial know-how and trade secrets relating to the development and commercialization of our cell engineering technology platforms and related product candidates, including related manufacturing processes and protocols.

Our intellectual property strategy is designed to provide multi-layered protection covering our T‑cell reprogramming technologies, including but not limited to c-Jun, NR4A3, Epi‑R and Stim‑R, as well as various aspects of our product candidates.

candidates, including related manufacturing processes and protocols.

Our intellectual property strategy is designed to provide multi-layered protection covering our technologies and manufacturing protocols, including but not limited to c-Jun, NR4A3, CD62L + enrichment, Epi‑R and Stim‑R, as well as various aspects of our product candidates, including but not limited to CAR constructs.

For all patent applications, we determine claiming strategy on a case-by-case basis.

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As of December 31, 2024, our patent portfolio consists of over 50 issued patents and over 250 pending patent applications that we either own or have licensed.

Our portfolio covers various aspects of our T‑cell reprogramming technologies, c-Jun, NR4A3, Epi‑R and Stim‑R, as well as our product candidates.

Our portfolio covers various aspects of our technologies and manufacturing protocols, including but not limited to c-Jun, NR4A3, CD62L + enrichment, Epi‑R and Stim‑R, as well as our product candidates.

The patents and patent applications in our portfolio are held primarily in the United States, Europe, Canada, Japan and Australia.

For information related to our in-licensed intellectual property, see the subsection titled under “—License, Collaboration and Success Payment Agreements.”

For information related to our in-licensed intellectual property, see the subsection titled under “—License and Collaboration Agreements.”

Individual patents extend for varying periods of time, depending upon the date of filing of the patent application, the date of patent issuance and the legal term of patents in the countries in which they are obtained.

Generally, patents issued for applications filed in the United States are effective for 20 years from the earliest nonprovisional filing date.

In the United States, a patent’s term may be lengthened by patent term adjustment (PTA), which compensates a patentee for administrative delays by the USPTO in examining and granting a patent or may be shortened if a patent is terminally disclaimed over an earlier filed patent.

In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S.

Patent and Trademark Office (USPTO) in examining and granting a patent or may be shortened if a patent is terminally disclaimed over an earlier filed patent.

In addition, in certain instances, the patent term of a U.S.

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The actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country and the validity and enforceability of the patent.

As of December 31, 2023, our registered trademark portfolio contains over 135 registered trademarks and pending trademark applications, consisting of approximately one trademark registration and five pending trademark applications in the United States, and approximately 120 foreign trademark registrations and approximately 11 foreign pending trademark applications.

As of December 31, 2024, our registered trademark portfolio contains over 135 registered trademarks and pending trademark applications, consisting of approximately one trademark registration and four pending trademark applications in the United States, and approximately 121 foreign trademark registrations and approximately 10 foreign pending trademark applications.

We may also rely, in some circumstances, on trade secrets to protect our technology.

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We seek to protect our technology and product candidates, in part, by entering into confidentiality agreements with those who have access to our confidential information, including our employees, contractors, consultants, collaborators and advisors.

We also seek to preserve the integrity and confidentiality of our proprietary technology and

processes by maintaining physical security of our premises and physical and electronic security of our information technology systems.

We also seek to preserve the integrity and confidentiality of our proprietary technology and processes by maintaining physical security of our premises and physical and electronic security of our information technology systems.

Although we have confidence in these individuals, organizations and systems, agreements or security measures may be breached and we may not have adequate remedies for any breach.

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Given our stage of development, we have not yet established a commercial organization or distribution capabilities.

We intend to either build a commercial infrastructure to support sales of any approved products or outsource some or all of this function to third parties.

We intend to evaluate opportunities to work with partners that enhance our capabilities with respect to the development and commercialization of LYL797, LYL845, LYL119 and any other product candidates we may develop.

We intend to either build a commercial infrastructure to support sales of any approved products or outsource

some or all of this function to third parties.

We intend to evaluate opportunities to work with partners that enhance our capabilities with respect to the development and commercialization of IMPT-314 and any other product candidates we may develop.

In addition, we intend to commercialize our product candidates, if approved, in key markets either alone or with partners to maximize the worldwide commercial potential of our programs.

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and any available human data or literature to support the use of the investigational product.

An IND must become effective before human clinical trials may begin.

An IND must become effective before human

clinical trials may begin.

The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises safety concerns or questions about the proposed clinical trial.

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Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.

• Phase 3—The investigational product is administered to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at

multiple geographically dispersed clinical trial sites.

These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval.

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A CRL will describe all of the deficiencies that the FDA has identified in the BLA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the CRL without first conducting required inspections, testing submitted product lots and/or reviewing proposed labeling.

In issuing the CRL, the FDA may recommend actions that the applicant might take to place the BLA in condition for

approval, including requests for additional information or clarification.

In issuing the CRL, the FDA may recommend actions that the applicant might take to place the BLA in condition for approval, including requests for additional information or clarification.

The FDA may delay or refuse approval of a BLA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.

If regulatory approval of a product is granted, such approval will be granted for particular indications and may entail limitations on the indicated uses for which such product may be marketed.

For example, the FDA may approve the BLA with a REMS, to ensure the benefits of the product outweigh its risks, or otherwise limit the scope of any approval.

For example, the FDA may approve the BLA with a Risk Evaluation and Mitigation Strategy (REMS), to ensure the benefits of the product outweigh its risks, or otherwise limit the scope of any approval.

A REMS is a safety strategy implemented to manage a known or potential serious risk associated with a product and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

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Once approved, the FDA may withdraw the product approval if compliance with pre- and post-marketing requirements is not maintained or if problems occur after the product reaches the marketplace.

The FDA may require one or more Phase 4 post-marketing trials and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization and may limit further marketing of the product based on the results of these post-marketing studies.

The FDA may require one or more Phase 4

post-marketing trials and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization and may limit further marketing of the product based on the results of these post-marketing studies.

Expedited Development and Review Programs

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The designation includes all of the Fast Track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product candidate, including involvement of senior managers.

Any marketing application for a drug or biologic submitted to the FDA for approval, including a product candidate with a fast track designation and/or breakthrough therapy designation, may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

Any marketing application for a drug or biologic submitted to the FDA for approval, including a product candidate with Fast Track and/or Breakthrough Therapy Designation, may be eligible for other types of FDA programs intended to expedite development and review, such as Priority Review and Accelerated Approval.

A product candidate 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.

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As a condition of Accelerated Approval, the FDA will generally require the sponsor to perform adequate and well-controlled post-marketing clinical trials to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit.

Products receiving accelerated approval may be subject to expedited

withdrawal procedures if the sponsor fails to conduct the required post-marketing studies or if such studies fail to verify the predicted clinical benefit.

Products receiving Accelerated Approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required post-marketing studies or if such studies fail to verify the predicted clinical benefit.

In addition, the FDA currently requires as a condition for Accelerated Approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

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RMAT designation provides all the benefits of Breakthrough Therapy Designation, including more frequent meetings with the FDA to discuss the development plan for the product candidate and eligibility for rolling review and Priority Review.

Product candidates granted RMAT designation may also be eligible for accelerated approval on the basis of a surrogate or intermediate endpoint reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of clinical trial sites, including through expansion of trials to additional sites.

Product candidates granted RMAT designation may also be eligible for Accelerated Approval on the basis of a surrogate or intermediate endpoint reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a

meaningful number of clinical trial sites, including through expansion of trials to additional sites.

RMAT-designated products that receive Accelerated Approval may, as appropriate, fulfill their post-approval requirements through submission of clinical evidence, clinical trials, patient registries or other sources of real-world evidence (such as electronic health records);

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or via post-approval monitoring of all patients treated with such therapy prior to approval of such therapy.

Fast Track Designation, Breakthrough Therapy Designations, Priority Review, Accelerated Approval and RMAT designation do not change the standards for approval but may expedite the development or approval process.

Fast Track, Breakthrough Therapy Designation, Priority Review, Accelerated Approval and RMAT designation do not change the standards for approval but may expedite the development or approval process.

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

Orphan Drug Designation and Exclusivity

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 individuals in the United States, or a patient population greater than 200,000 individuals in the United States and when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the United States will be recovered from sales in the United States for that drug or biologic.

Orphan Drug designation (ODD) must be requested before submitting a BLA.

Under the Orphan Drug Act, the FDA may grant Orphan Drug Designation (ODD) to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 individuals in the United States, or a patient population greater than 200,000 individuals in the United States and when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the United States will be recovered from sales in the United States for that drug or biologic.

ODD must be requested before submitting a BLA.

After the FDA grants ODD, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

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Orphan product exclusivity also could block the approval of one of our products for seven years if a competitor obtains approval of the same biological product as defined by the FDA or if our product candidate is determined to be contained within the competitor’s product for the same indication or disease.

A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the indication for which it received orphan designation.

A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the indication for which it received the ODD.

In addition, Orphan Drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or, as noted above, if a second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

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Biologics are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution and advertising and promotion of the product.

After approval, most changes to the approved product, such as

adding new indications or other labeling claims, are subject to prior FDA review and approval.

After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval.

There also are continuing, annual program fees for any marketed products.

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The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with

regulatory requirements, may result in revisions to the approved labeling to add new safety information;

imposition of post‑market studies or clinical trials to assess new safety risks;

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In addition, the approval of a biosimilar product may not be made effective by the FDA until twelve (12) years from the date on which the reference product was first licensed.

During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own nonclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product.

data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product.

The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products.

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Such laws include, without limitation, federal and state anti-kickback, fraud and abuse, false claims, data privacy and security, price reporting and physician and other health care provider transparency laws and regulations.

If our operations are found to be in violation of any of such laws or any other governmental

regulations that apply, we may be subject to penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations, integrity oversight and reporting obligations, exclusion from participation in federal and state healthcare programs and imprisonment.

If our operations are found to be in violation of any of such laws or any other governmental regulations that apply, we may be subject to penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations, integrity oversight and reporting obligations, exclusion from participation in federal and state healthcare programs and imprisonment.

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 or service reimbursable under Medicare, Medicaid or other federal healthcare programs.

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The exceptions and safe harbors are drawn narrowly and practices that involve remuneration that may be alleged to be intended to induce prescribing, purchasing or recommending may be subject to scrutiny if they do not qualify for an exception or safe harbor but the exceptions and safe harbors are drawn narrowly and require strict compliance in order to offer protection.

Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute.

Failure to meet all of the requirements of a particular applicable statutory exception or regulatory

safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute.

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

Additionally, the intent standard under the Anti-Kickback Statute and the criminal healthcare fraud statutes under the federal Health Insurance Portability and Accountability Act of 1996 (HIPAA) was amended by the ACA to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

Additionally, the intent standard under the Anti-Kickback Statute and the criminal healthcare fraud statutes under the federal Health Insurance Portability and Accountability Act of 1996 (as amended by the Health Information Technology for Economic and Clinical Health Act, HIPAA) was amended by the ACA to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

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

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Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

Additionally, the federal Physician Payments Sunshine Act within the ACA, 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 related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other health care professionals (such as physician assistants and nurse practitioners) and teaching hospitals and certain ownership and investment interests held by these physicians and their immediate family members.

Additionally, the federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers of commercial 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 related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other health care professionals (such as physician assistants and nurse practitioners) and teaching hospitals and certain ownership and investment interests held by these physicians and their immediate family members.

We may also be subject to data privacy and security regulations by both the federal government and the states in which we conduct our business.

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Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to business associates, 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.

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.

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Some states also impose requirements on manufacturers and distributors to establish the pedigree of product in the chain of distribution, including some states that require manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain.

Several states have enacted legislation requiring pharmaceutical companies to establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, track and report gifts, compensation and other remuneration made to physicians and other healthcare providers, clinical trials and other activities, and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician prescribing data to pharmaceutical companies for use in sales and marketing, and to prohibit certain other sales and marketing practices.

pharmaceutical companies for use in sales and marketing, and to prohibit certain other sales and marketing practices.

All of our activities are potentially subject to federal and state consumer protection and unfair competition laws.

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In the United States, in March 2010, the ACA was enacted, which substantially changed the way healthcare is financed by both governmental and private insurers, and significantly affected the pharmaceutical industry.

The ACA contained a number of provisions, including those governing enrollment in federal healthcare programs, reimbursement adjustments and changes to fraud and abuse laws.

For example, the ACA:

increased the minimum level of Medicaid rebates payable by manufacturers of brand name drugs from 15.1% to 23.1%;

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

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 eligibility criteria for Medicaid programs;

created a 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 and Medicaid Innovation at CMS (CMMI) to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.

There have been executive, judicial and Congressional challenges to certain aspects of the ACA.

For example, the Tax Act was enacted, which includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” On June 17, 2021, the U.S.

Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress.

President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructs certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

Further, 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 ACA marketplaces through plan year 2025.

There have been executive, judicial and Congressional challenges and amendments to certain aspects of the ACA.

Further, on August 16, 2022, the Inflation Reduction Act of 2022 (the IRA) was signed into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost through a newly established manufacturer discount program.

It is possible that the ACA will be subject to judicial or Congressional challenges in the future.

It is unclear how any such additional challenges and healthcare reform measures of the Biden administration will impact the ACA and our business.

It is possible that the ACA will be subject to additional challenges in the future.

It is unclear how any such additional challenges and healthcare reform measures of the second Trump administration will impact the ACA and our business.

Other legislative changes have also been proposed and adopted in the United States since the ACA was enacted.

On August 2, 2011, the Budget Control Act of 2011, among other things, included aggregate reductions to Medicare payments to providers of 2% per fiscal year, which began in 2013 and will remain in effect through 2032.

In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

There has been heightened governmental scrutiny recently over the manner in which pharmaceutical companies set prices for their marketed products, which has resulted in several Congressional inquiries and proposed federal legislation, as well as state efforts, designed to, among other things, bring more transparency to product pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.

In addition, the IRA, among other things, (1) directs HHS to negotiate the price of certain single-source drugs and biologics covered under Medicare and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions 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.

It is currently unclear how the IRA will be implemented, but it is likely to have a significant impact on the pharmaceutical industry.

Further 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 CMMI, 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 of 1980 (Bayh-Dole Act).

In addition, the IRA, among other things, (1) directs HHS to negotiate the price of certain high-expenditure, single-source biologics that have been on the market for at

least eleven years covered under Medicare (the Medicare Drug Price Negotiation Program) and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions began to take effect progressively in fiscal year 2023, although the Medicare Drug Price Negotiation Program is currently subject to legal challenges.

On August 15, 2024, HHS announced the agreed-upon prices of the first ten drugs that were subject to price negotiations which take effect in January 2026.

On January 17, 2025, HHS selected fifteen additional products covered under Part D for price negotiation in 2025.

Each year thereafter more Part B and Part D products will become subject to the Medicare Drug Price Negotiation Program.

Further, on December 7, 2023, an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act of 1980 (Bayh-Dole Act) was announced.

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 that for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.

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At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological 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.

We anticipate that these new laws will result in additional downward pressure on coverage and the price that we receive for any approved product, and could seriously harm our business.

These health reform measures will result in additional downward pressure on coverage and the price that we receive for any approved product and could seriously harm our business.

Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private payors.

The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain

profitability or commercialize our products (if approved).

In addition, it is possible that there will be further legislation or regulation that could harm our business, financial condition and results of operations.

For example, it is possible that additional governmental action may be taken to address another health epidemic, as it did in response to the COVID-19 pandemic.

The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our products (if approved).

In addition, it is possible that there will be further legislation or regulation that could harm our business, financial condition and results of operations, particularly in light of the recent U.S.

Presidential and Congressional elections.

Other Data Privacy and Security Laws

In the ordinary course of our business, we may process or receive personal or sensitive data.

In the ordinary course of our business, we process or receive personal or sensitive data.

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 and security in the jurisdictions in which we are established or in which we sell or market any approved products or run clinical trials.

Such obligations may include those from, without limitation, the Federal Trade Commission Act, the California Consumer Privacy Act of 2018 (CCPA), the California Privacy Rights Act (CPRA), the European Union’s General Data Protection Regulation 2016/679 (EU GDPR), the EU GDPR as it forms part of United Kingdom (UK) law by virtue of section 3 of the European Union (Withdrawal) Act 2018 (UK GDPR) and the ePrivacy Directive.

Such obligations may include those from, without limitation, the Federal Trade Commission Act, the California Consumer Privacy Act of 2018, as amended by the California Privacy Rights Act of 2020 (CPRA) (collectively, CCPA), the EU’s General Data Protection Regulation 2016/679 (EU GDPR), the EU GDPR as it forms part of UK law by virtue of section 3 of the European Union (Withdrawal) Act 2018 (UK GDPR) and the ePrivacy Directive.

Several states within the United States have also enacted or proposed data privacy and security laws.

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As one example, the EU GDPR applies to any company established in the European Economic Area, which is comprised of the 27 Member States of the EU plus Norway, Iceland and Liechtenstein (collectively, the EEA) and to companies established outside the EEA that process personal data in connection with the offering of goods or services to data subjects in the EEA or the monitoring of the behavior of data subjects in the EEA.

These obligations may include limiting personal data processing to only what is necessary for specified, explicit and legitimate purposes;

These obligations include limiting personal data processing to only what is necessary for specified, explicit and legitimate purposes;

requiring a legal basis for personal data processing;

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formalizing a heightened and codified standard of data subject consents;

requiring the implementation and maintenance of technical and organizational safeguards for personal data;

the implementation and maintenance of technical and organizational safeguards for personal data;

mandating notice of certain personal data breaches to the relevant supervisory authorities and affected individuals;

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Employees and Human Capital Management

We are a clinical stage T‑cell reprogramming company dedicated to developing novel cell therapies to improve the lives of people with malignant solid tumors.

We are a clinical cell therapy company entering pivotal trials and advancing a pipeline of proprietary next‑generation CAR T-cell product candidates for patients with cancer.

We are pioneering novel approaches designed to generate T cells that drive long-lasting clinical response.

We strive to create an environment where everyone can do their best work, be themselves and thrive personally and professionally.

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We challenge the status quo – we are bold and willing to think and act differently.

We always assume positive intent and seek to understand and communicate directly, transparently and honestly.

We operate with positive intent and seek to understand and communicate directly, transparently and honestly.

• Collaboration :

We work together to create value, working across teams to solve our most challenging problems to continually improve and learn.

In 2024, with active participation from our employees, we created behavior expectations to describe how Lyellites demonstrate our values at work.

Leaders and employees attended workshops where we defined behavior statements that have been embedded in our performance management and development programs.

These behaviors exemplify our values as well as principles of patient-centricity, innovation and inclusion.

Our Employees

Our employees are one of our most valuable strengths;

our people drive our ability to achieve our mission.

We compete in the highly competitive biotechnology industry, and attracting, retaining and developing a diverse group of talented employees is crucial to our strategy and our ability to compete effectively.

Our organization is designed to support our current research, product development and manufacturing efforts and is ready to scale to meet future plans for commercializing our product candidates, if approved.

A strategic priority is attracting and retaining talent with the skills we need today and in the future.

Our people drive our mission.

We compete in the highly competitive biotechnology industry, and attracting, retaining and developing a diverse group of talented employees is crucial to our strategy and we believe is a competitive advantage.

Our organization is designed to support research, product development and manufacturing efforts and is ready to scale to meet future plans for commercializing our product candidates, if approved.

A strategic priority is attracting and retaining talent with the skills we need now and in the future.

The labor market continues to reflect a limited pool of skilled individuals with substantial experience discovering, developing and manufacturing cell therapy medicines, and we expect this is likely to continue.

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Many of our employees have experience with the development of cell therapies.

All of our employees are located in California and Washington.

The majority of our employees are located in California and Washington, with all employees based in the United States.

None of our employees are subject to a collective bargaining agreement nor represented by labor unions.

We consider our relationship with our employees to be good.

Developing our employees is important, and we focus on providing training and opportunities for development and advancement.

Developing our employees is important, and we focus on providing learning opportunities for development and advancement.

Training, coaching, routine feedback and a systematic approach to employee advancement are key components of our talent strategy.

We hold talent discussions regularly, which include promotion cycles across all functions and levels.

In 2023, we have further enhanced our talent management practices, including establishing career frameworks for development positions, implementing individual goal setting for all staff and introducing a compensation approach that recognizes differentiated performance.

We hold talent discussions regularly, which include leaders identifying talent for promotion across all functions.

Foundations of our talent management practice include career frameworks for progression and development, individual goal setting for all staff including one development goal to continue to improving skills and abilities in the current role and a compensation approach that recognizes differentiated performance and shares performance feedback regularly.

In 2024, we participated in the Great Place to Work survey for the first time and, based on employee responses to the survey, we received certification as a Great Place to Work.

With 81% of employees participating in the survey, we received high ratings in multiple areas, with engagement, culture, inclusion and innovation being specific areas of strength.

Employee feedback, through independent and anonymous surveys, provide us with the data on an ongoing basis that we need to ensure that our leadership, culture and people practices are supporting the talented workforce that we need to advance our mission.

Since inception, our employee turnover has remained consistently below average for the U.S.

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Given the highly competitive nature of our industry and the importance of recruitment and retention to our success, we strive to provide our employees with what we believe is a competitive and comprehensive total rewards package of compensation, benefits and services.

This package includes competitive market pay, healthcare benefits for employees and family members, a flexible spending account, paid time off benefits, family leave, flexible work schedules, flexible work locations, 401(k) matching, an employee assistance program and a wellness program.

In addition, we offer

employees the benefit of equity ownership in the company through stock option grants and/or restricted stock units.

This package includes competitive market pay, healthcare benefits for employees and family members, a flexible spending account or health savings account, paid time off benefits, family leave, flexible work schedules, flexible work locations, 401(k) matching, an employee assistance program and a wellness program.

In addition, we offer employees the benefit of equity ownership in the company through stock option grants and/or restricted stock units.

Our employees are also eligible to participate in an employee stock purchase plan, which offers the opportunity to purchase our common stock at a discount of 15%.

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The DBIE working group is guided by a collaboratively developed DBIE mission statement.

The working group is comprised of volunteers from our three work locations representing various levels in the organization.

The working group is comprised of volunteers across each of our work locations representing various levels in the organization.

This team, sponsored by our Chief Executive Officer and Senior Vice President of Human Resources, creates an annual strategic and tactical plan to advance our focus on the importance of DBIE to our culture.

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Recruitment, progression and development processes emphasize the importance of fostering a workforce that is representative of our diverse patient population.

While we are proud of our progress to date, we have and will continue to conduct relevant training and provide guidance with respect to best practices of similarly situated companies.

Employee feedback from our Great Place to Work survey rated the organization very high on four key questions on inclusion:

(1) People here are treated fairly regardless of their sexual orientation;

(2) People here are treated fairly regardless of their race;

(3) People here are treated fairly regardless of their gender;

and (4) People here are treated fairly

regardless of their age.

We continue to evolve our workplace practices to ensure that our culture embeds fair treatment for all and is seen as a place where individuals can be their authentic selves at work.

We have plans to continue to build on our early years and continue to mature our DEI strategy and practices in the years ahead working from this strong foundation.

We believe in equitable pay and our compensation practices are reviewed regularly.

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Ongoing pay progression is guided by our compensation philosophy;

in 2023, this was enhanced to recognize differentiation in rewards, where our highest performing employees received the highest rewards.

we recognize differentiation in rewards, where our highest performing employees receive the highest rewards.

At the same time, we are committed to pay equity;

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Available Information

We were incorporated in June 2018 under the laws of the state of Delaware.

Our website address is www.lyell.com.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business