UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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| Item 7.01. | Regulation FD Disclosure. |
On June 26, 2024, Lyell Immunopharma, Inc. issued a press release (the “LYL797 Phase 1 Press Release”) to report initial clinical and translational data from its Phase 1 clinical trial of LYL797, its intravenously-administered chimeric antigen receptor (“CAR”) T-cell product targeting the receptor tyrosine kinase-like orphan receptor 1 (“ROR1”) protein. A copy of the LYL797 Phase 1 Press Release is furnished hereby as Exhibit 99.1 and is incorporated herein by reference.
| Item 8.01. | Other Events. |
On June 26, 2024, Lyell announced initial clinical and translational data from its Phase 1 trial of LYL797, a ROR1 CAR T-cell product candidate enhanced with Lyell’s proprietary anti-exhaustion technology, for the treatment of advanced solid tumors. These initial data from 20 treated patients included 16 patients with triple-negative breast cancer (“TNBC”) and 4 patients with non-small cell lung cancer. All patients enrolled had relapsed/refractory metastatic disease and the mean lines of prior therapies for metastatic disease was six. Four dose levels, including two interim dose levels, have been explored to date: 50 x 106 cells, 100 x 106 cells, 150 x 106 cells and 300 x 106 cells. There were 16 efficacy evaluable patients, and 18 safety evaluable patients included in the initial data set. Patients with TNBC treated with LYL797 had an objective response rate (“ORR”) of 40% and a clinical benefit rate (“CBR”) of 60% at the 150 x 106 CAR T cell dose level, the highest dose level cleared to-date, with a CBR of 38% across all dose levels evaluable to date. The most frequently reported related adverse events of any grade included cytokine release syndrome (61%, Grade 1 and 2), pneumonitis (22%), headache (17%), and cytopenia from lymphodepletion. The most frequently reported Grade ≥ 3 related adverse events were pneumonitis (17%) and hypoxia (11%), as well as the expected cytopenia from lymphodepletion in 78% of patients. One patient had Grade 5 respiratory failure on Day 41. There were no reports of immune effector cell-associated neurotoxicity syndrome (“ICANS”) attributed to LYL797. The instances of pneumonitis occurred in patients with lung metastases, and Lyell is continuing dose escalation separately and more gradually in those patients. No dose-limiting toxicities have been reported in patients without lung involvement. All patients are now receiving prophylactic steroids prior to LYL797 treatment. Translational data from a subset of patients demonstrated that CAR T cells enhanced with anti-exhaustion technology expanded, infiltrated and persisted into solid tumors, in some cases with associated evidence of tumor killing. LYL797 CAR T-cell expansion was observed in peripheral blood samples at Day 60 in all patients assessed to date (n = 11), with peak expansion occurring between Days 8 and 11. Median peak expansion was about three-fold higher in patients receiving 150 x 106 cells compared to those receiving 50 x 106 cells. The exhaustion marker, TIGIT, was found in a low proportion of LYL797 CAR T cells at Day 11 (n = 4), providing support for the role of c-Jun overexpression as an anti-exhaustion technology. A significant proportion of cells with stem-like and effector memory phenotypes were demonstrated at Days 11 and 22 following RNAseq transcriptomic analysis supporting the role of Epi-R to preserve a stem-like phenotype. LYL797 CAR T cells were present in all evaluable solid-tumor biopsies (n = 9). An additional sample collected confirmed CAR T cell persistence more than four months post treatment. Collectively, these initial data indicate that LYL797 CAR T cells enhanced with Lyell’s anti-exhaustion technology were able to infiltrate and persist in the solid tumor microenvironment.
A copy of the presentation related to the LYL797 Phase 1 clinical trial is posted on the Company’s website and is filed herewith as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated by reference herein.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits.
| Exhibit No |
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| 99.1 | Press Release, dated June 26, 2024, titled “Lyell Immunopharma Reports Dose-dependent Clinical Activity from Phase 1 Trial of LYL797, a ROR1-targeted CAR-T Cell Product Candidate Enhanced with its Proprietary Anti-exhaustion Technology.” | |
| 99.2 | Lyell Immunopharma, Inc. Presentation dated June 2024 | |
| 104.1 | Cover Page Interactive Data File, formatted in inline XBRL. | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.
| Lyell Immunopharma, Inc. | ||||||
| Date: June 26, 2024 | By: | /s/ Matthew Lang | ||||
| Matthew Lang | ||||||
| Chief Business Officer | ||||||
Exhibit 99.1
Lyell Immunopharma Reports Dose-dependent Clinical Activity from Phase 1 Trial of LYL797, a ROR1-targeted CAR-T Cell Product Candidate Enhanced with its Proprietary Anti-exhaustion Technology
| • | Dose-dependent antitumor clinical activity in ROR1+ relapsed/refractory triple-negative breast cancer; 40% objective response rate and 60% clinical benefit rate at the highest dose cleared to date (150 x 106 CAR T cells) |
| • | First demonstration that CAR T cells enhanced with anti-exhaustion technology can both expand and infiltrate into solid tumors |
| • | No significant safety signal related to LYL797 observed in patients without lung involvement; treatable pneumonitis observed in patients with lung metastatic disease; dose escalation continues in separate cohorts |
| • | Expanding development into new tumor types including ROR1+ relapsed/refractory platinum-resistant ovarian cancer, endometrial cancer, multiple myeloma and chronic lymphocytic leukemia |
| • | IND submission completed for LYL119, Lyell’s next generation ROR1-targeted CAR T cell product candidate |
| • | Investor Webcast with David R. Spigel, MD, Chief Scientific Officer at the Sarah Cannon Research Institute and a lead investigator in the Phase 1 clinical trial, scheduled for 8:30 am ET today |
SOUTH SAN FRANCISCO, Calif., June 26, 2024 — Lyell Immunopharma, Inc. (Nasdaq: LYEL), a clinical-stage T-cell reprogramming company advancing a diverse pipeline of cell therapies for patients with solid tumors, today announced initial clinical and translational data from its Phase 1 trial of LYL797, its first-generation reprogrammed ROR1 CAR T-cell product candidate enhanced with proprietary anti-exhaustion technology. The initial dataset consists primarily of patients with triple-negative breast cancer (TNBC) and demonstrated dose-dependent antitumor clinical activity and the ability of LYL797 CAR T cells to proliferate, infiltrate tumors and kill cancer cells in patients with relapsed/refractory disease. Patients with TNBC treated with LYL797 had an objective response rate (ORR) of 40% and clinical benefit rate (CBR) of 60% at the 150 x 106 CAR T cell dose level, with a CBR of 38% across all dose levels evaluable to date. Common treatment-related adverse events in patients without lung metastases included Grade 1 and 2 cytokine release syndrome (CRS) and headache, and the expected cytopenia from lymphodepletion. There were no reports of immune effector cell-associated neurotoxicity syndrome (ICANS) attributed to LYL797. Pneumonitis occurred in patients with lung metastases and dose escalation is continuing separately and more gradually in those patients. No dose-limiting toxicities have been reported in patients without lung involvement. All patients are now receiving prophylactic steroids prior to LYL797 treatment.
“These are promising initial clinical findings demonstrating that LYL797 ROR-1-targeted CAR T cells had dose-dependent antitumor clinical activity and have the potential to deliver even more meaningful and durable benefit to patients as we continue to dose escalate,” said David R. Spigel, MD, Chief Scientific Officer at the Sarah Cannon Research Institute, medical oncologist and a lead investigator in the LYL797 study. “Pneumonitis is a known complication of radiotherapy and several approved cancer therapies, including immune checkpoint blockade and several antibody-drug conjugate therapies. We have implemented a protocol using steroids, the standard of care for treatment of patients with pneumonitis, that I believe will enable us to successfully monitor and manage these events.”
The LYL797 study includes a robust translational program from which Lyell reports the first demonstration that CAR T cells enhanced with anti-exhaustion technology expanded, persisted and infiltrated into solid tumors, in some cases with associated evidence of cancer cell killing. TIGIT, a marker of T cell exhaustion, was measured in samples collected on Day 11 post-infusion with only a low proportion of LYL797 CAR T cells demonstrated to be TIGIT-positive. RNAseq data also suggested a significant proportion maintained the targeted stem-like and effector memory cell phenotype.
“We are encouraged to see clinical responses and a clear dose-dependent indication of antitumor clinical activity from treatment with LYL797 in patients with advanced triple-negative breast cancer,” said Lynn Seely, MD, President and Chief Executive Officer of Lyell. “Our translational data provide, to our knowledge, the first demonstration of persistent CAR T cell infiltration into solid tumors associated with evidence of cancer cell killing. This early validation of our anti-exhaustion technology gives us the conviction to expand our trial to include patients with ROR1+ ovarian or endometrial cancers, while continuing to enroll patients with triple-negative breast or non-small lung cancers, and also to initiate a new clinical trial for patients with multiple myeloma and chronic lymphocytic leukemia. This compelling early clinical data from LYL797 gives us a high degree of confidence to advance LYL119, our next generation ROR1-targeted product candidate with even more powerful anti-exhaustion technology. We have submitted an IND for LYL119 and expect to enter the clinic this year.”
Initial LYL797 Phase 1 Clinical Trial Results
This initial dataset of 20 treated patients includes 16 patients with TNBC and four patients with non-small cell lung cancer. All patients enrolled had relapsed/refractory metastatic disease and the mean lines of prior therapies for metastatic disease was six. Four dose levels, including two interim dose levels, have been explored to date: 50 x 106 cells, 100 x 106 cells, 150 x 106 cells and 300 x 106 cells. The efficacy evaluable subset includes 16 patients, and the safety evaluable subset includes 18 patients. The manufacturing success rate was 100%.
Of the five patients with TNBC treated with LYL797 at the 150 x 106 cell dose level, the highest dose level cleared to date, two patients had confirmed partial responses to Day 90, resulting in an ORR of 40%. The CBR, defined as a best response of stable disease, partial response or complete response, was dose-dependent with 60% at the 150 x 106 cell dose level and 38% across all four dose levels evaluated.
The most frequently reported related adverse events of any grade are CRS (61%), pneumonitis (22%) and headache (17%), as well as the expected cytopenia from lymphodepletion in all patients. The CRS was generally mild (Grade 1 or 2 only), characterized by fever, and treated with tocilizumab and steroids. There were no reports of immune effector cell-associated neurotoxicity syndrome (ICANS) attributed to LYL797. The most frequently reported Grade > 3 related adverse events were pneumonitis (17%) and hypoxia (11%), as well as the expected cytopenia from lymphodepletion in 78% of patients. One patient had Grade 5 respiratory failure on Day 41. The adverse event of Grade > 3 pneumonitis occurred only in patients with TNBC and lung metastases, resulting in the separation of dose escalation into two cohorts based upon lung involvement (lung primary, lung metastatic disease or pleural effusion). No dose-limiting toxicities occurred in patients without lung involvement. All patients are now receiving prophylactic therapy with dexamethasone to mitigate pneumonitis. Patients without lung involvement are currently under evaluation at the 300 x 106 cell dose level and patients with lung involvement are currently under evaluation at 75 x 106 cell dose level.
Translational data are described on a subset of patients and include CAR T cell expansion in peripheral blood, phenotypic analysis of T cell exhaustion and stem-like markers and on-study tumor biopsies to assess for CAR T cell tumor infiltration. LYL797 CAR T-cell expansion was observed in peripheral blood samples at Day 60 in all patients assessed to date (n = 11) with peak expansion occurring between Days 8 and 11. Peak expansion was on average three-fold higher in patients receiving 150 x 106 cells compared to those receiving 50 x 106 cells. The exhaustion marker, TIGIT, was found only in a low proportion of LYL797 CAR T cells at Day 11 (n = 4) providing support for the role of c-Jun overexpression as an anti-exhaustion technology. A significant proportion of cells with stem-like and effector memory phenotypes were demonstrated at Days 11 and 22 following RNAseq transcriptomic analysis supporting the role of Epi-R to preserve a stem-like phenotype. Nine evaluable on-treatment tumor biopsies collected between Days 21 and 30 after LYL797 infusion were assessed. LYL797 CAR T cells were present in all solid-tumor biopsies, indicating that LYL797 CAR T cells enhanced with Lyell’s anti-exhaustion technology were able to infiltrate and persist in the solid tumor microenvironment. In addition, the tumor biopsies have features consistent with T cell-mediated tumor lysis, including T cell-rich inflammation with scattered tumor cells.
Conference Call and Webcast Details
Lyell’s management, together with David R. Spigel, MD, Chief Scientific Officer at the Sarah Cannon Research Institute and a lead investigator in the Phase 1 clinical trial, will host an investor conference call and Webcast beginning at 8:30 am ET today, to discuss the initial data from the LYL797 Phase 1 clinical trial.
| • | The Webcast can be accessed here. |
| • | To join the live conference call, please register here to receive a dial-in number and unique PIN to access the call. |
It is recommended callers join ten minutes prior to the start of the event (although you may register and join at any time during the Webcast). A replay of the event and presentation materials will be archived on the Investor page of the Lyell Website following the end of the event.
LYL797 Phase 1 Clinical Trial Design (NCT05274451)
The Phase 1 clinical 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 NSCLC who have failed at least one line of therapy. The trial has been amended to also include patients with platinum-resistant ovarian cancer or endometrial cancer. All patients enrolled have tumor specimens positive for ROR1 protein expression by immunohistochemistry.
More information on the Phase 1 trial can be found on clinicaltrials.gov here.
About LYL797
LYL797 is a receptor tyrosine kinase-like orphan receptor 1 (ROR1) -targeted CAR T-cell product candidate enhanced with Lyell’s anti-exhaustion genetic reprogramming technology (c-Jun) and epigenetic reprogramming technology (Epi-R). LYL797 overexpresses c-Jun to correct for an imbalance in the AP-1 family of transcription factors present in exhausted T cells. In preclinical studies, overexpression of c-Jun enables T cells to resist exhaustion, infiltrate solid tumors and maintain their functionality. LYL797 is manufactured utilizing Epi-R, Lyell’s 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.
ROR1 is a fetal protein expressed during embryogenesis and is believed to be important in cell migration, polarity and survival. Significant subsets of patients with common cancers express ROR1 and it is generally associated with a poor prognosis.
About Lyell Immunopharma, Inc.
Lyell is a clinical-stage T-cell reprogramming company advancing a diverse pipeline of cell therapies for patients with solid tumors. Lyell is currently enrolling a Phase 1 clinical trial evaluating a first-generation ROR1-targeted CAR T-cell therapy enhanced with anti-exhaustion technology in patients with relapsed/refractory triple-negative breast cancer, non-small cell lung cancer (NSCLC), ovarian cancer and endometrial cancer. A second Phase 1 clinical trial is ongoing to evaluate reprogrammed tumor infiltrating lymphocytes (TIL) in patients with advanced melanoma, NSCLC and colorectal cancer. An investigational new drug application has been submitted to the FDA for LYL119, a next-generation ROR1-targeted CAR T-cell product candidate with even more powerful anti-exhaustion technologies.
The technologies powering Lyell’s product candidates are designed to address barriers that limit consistent and long-lasting responses to cell therapy for solid tumors: T-cell exhaustion and lack of durable stemness, which includes the ability to persist and self-renew to drive durable tumor cytotoxicity. Lyell is applying its proprietary ex vivo genetic and epigenetic reprogramming technologies to address these barriers to develop new medicines with improved durable clinical outcomes. Lyell is based in South San Francisco, California with facilities in Seattle and Bothell, Washington. To learn more, please visit www.lyell.com.
Forward Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding: the continued clinical progress of the LYL797 trials; the effectiveness of prophylactic steroids or other treatments to mitigate adverse events; the potential to deliver more meaningful and durable benefit to patients with dose escalation; Lyell’s plans to enroll patients with platinum-resistant ovarian cancer and endometrial cancer in the LYL797 trial; Lyell’s plans to submit an IND for LYL797 to initiate a new Phase 1 study evaluating LYL797 in patients with multiple myeloma or chronic lymphocytic leukemia and the timing thereof; Lyell’s development plans for LYL119 and the effectiveness of any technologies incorporated into LYL119; the ability of Lyell’s reprogramming technologies to infiltrate and persist in the solid tumor microenvironment; and other statements that are not historical fact. These statements are based on Lyell’s current plans, objectives, estimates, expectations and intentions, are not guarantees of future performance and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, but are not limited to, risks and uncertainties related to: macroeconomic conditions, including the effects of geopolitical instability and actual or perceived changes in interest rates and economic inflation; Lyell’s ability to submit planned INDs, obtain approval of submitted INDs, or initiate or progress clinical trials on the anticipated timelines, if at all; the potential for results from clinical trials to differ from nonclinical, early clinical, preliminary or expected results; Lyell’s limited experience as a company in enrolling and conducting clinical trials, and lack of experience in completing clinical trials; Lyell’s ability to manufacture and supply its product candidates for its clinical trials; the nonclinical profiles of Lyell’s product candidates or technology not translating in clinical trials; significant adverse events, toxicities or other undesirable side effects associated with Lyell’s product candidates; the significant uncertainty associated with Lyell’s product candidates ever receiving any regulatory approvals; Lyell’s ability to obtain, maintain or protect intellectual property rights related to its product candidates; implementation of Lyell’s strategic plans for its business and product candidates; the sufficiency of Lyell’s capital resources and need for additional capital to achieve its goals; and other risks, including those described under the heading “Risk Factors” in Lyell’s Annual Report on Form 10-K for the year ended December 31, 2023, filed with the Securities and Exchange Commission (SEC) on February 28, 2024, and the Quarterly Report on Form 10-Q for the quarter ended March 31, 2024, filed with the SEC on May 6, 2024. Forward-looking statements contained in this press release are made as of this date, and Lyell undertakes no duty to update such information except as required under applicable law.
Contact:
Ellen Rose
Senior Vice President, Communications and Investor Relations
erose@lyell.com
Exhibit 99.2 Initial Clinical and Translational Data from Phase 1 Trial of LYL797, an Enhanced ROR1-targeted CAR-T Cell Product Candidate June 26, 2024 1
Forward Looking Statements Certain matters discussed in this presentation are “forward-looking statements” of Lyell Immunopharma, Inc. (hereinafter referred to as the “Company,” “we,” “us,” or “our”) within the meaning of the Private Securities Litigation Reform Act of 1995 (the “PSLRA”). All such written or oral statements made in this presentation are forward-looking statements, including expansion of clinical trials in other indications, plans for dose escalation, Lyell’s plans to submit an IND for LYL797 and the timing thereof, the ability of Lyell’s reprogramming technologies to infiltrate and persist in the solid tumor microenvironments, indicative milestones and other statements that are not statements of historical fact, and are intended to be covered by the safe harbor for forward- looking statements provided by the PSLRA. Without limiting the foregoing, we may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” plans“,” “intends,” “forecast,” “guidance,” “outlook,” “may,” “could,” “might,” “will,” “should” or other words that convey uncertainty of future events or outcomes and are intended to identify forward-looking statements. Forward-looking statements are based on assumptions and assessments made in light of management’s experience and perception of historical trends, current conditions, expected future developments and other factors believed to be appropriate. Forward looking statements in this presentation are made as of the date of this presentation, and we undertake no duty to update or revise any such statements, whether as a result of new information, future events or otherwise. Forward-looking statements are not guarantees of future performance and are subject to risks, uncertainties and other factors, many of which are outside of our control, that may cause actual results, levels of activity, performance, achievements, timelines and developments to be materially different from those expressed in or implied by these forward-looking statements. Important factors that could cause actual results, developments and business decisions to differ materially from forward-looking statements are described in the sections titled “Risk Factors“ in our filings with the Securities and Exchange Commission (the “SEC”), and include, but are not limited to, the following substantial known and unknown risks and uncertainties inherent in our business related to: the effects of geopolitical instability; macroeconomic conditions, including the effects of geopolitical instability and actual or perceived changes in interest rates and economic inflation; our ability to initiate or progress our current and planned clinical trials or to submit planned INDs on the anticipated timelines, if at all; the potential for results from clinical trials to differ from nonclinical, early clinical, preliminary or expected results; our limited experience as a company in enrolling, conducting or completing clinical trials; our ability to manufacture and supply our product candidates for our clinical trials; significant adverse events, toxicities or other undesirable side effects associated with our product candidates; the significant uncertainty associated with our product candidates ever receiving any regulatory approvals; our ability to obtain, maintain, or protect intellectual property rights related to our product candidates; implementation of our strategic plans for our business and product candidates; the sufficiency of our capital resources and the need for additional capital to achieve our goals; other risks, including general economic conditions and regulatory developments, not within our control; and those risks described under the heading “Risk Factors” in our SEC filings, including our Quarterly Report on Form 10-Q for the quarter ended March 31, 2024 and subsequent filings with the SEC. This presentation concerns product candidates and technologies that are under clinical investigation, and which have not yet been approved for marketing by the U.S. Food and Drug Administration. These are currently limited by federal law to investigational use, and no representation is made as to their safety or effectiveness for the purposes for which they are being investigated. 2 ©2024 Lyell Immunopharma, Inc.
LYL797 Clinical Data Summary and Background Lynn Seely, MD President and Chief Executive Officer 3
LYL797 Initial Clinical Data and Progress Update Dose-Dependent Clinical Activity Observed • 40% Objective Response Rate, including 2 confirmed partial responses, at 150M CAR T cell dose (n=5), the highest dose level cleared to date – Clinical Benefit Rate of 60% at 150M CAR T cell dose and 38% across all dose levels • LYL797 CAR T cells successfully expanded, infiltrated solid tumors and killed cancer cells – First clinical demonstration of robust CAR T cell solid tumor infiltration Dose Escalation Ongoing Separately in Patients With or Without Lung Involvement • No DLTs in patients without lung involvement; 300M cell dose under evaluation • Pneumonitis observed in patients with lung involvement; dose escalation continuing with dexamethasone prophylaxis; treatable with steroids; 75M cell dose under evaluation Expanding into Additional ROR1-expressing Tumor Types Given Clinical Activity • Expanding into ovarian and endometrial cancers • Initiating a new clinical trial of LYL797 in multiple myeloma and chronic lymphocytic leukemia • IND submitted for LYL119, a next-generation ROR1-targeted product candidate 4 ©2024 Lyell Immunopharma, Inc. Data cutoff of 29 May 2024; CAR, chimeric antigen receptor; DLTs, dose-limiting toxicities; ROR1, receptor tyrosine kinase-like orphan receptor
Fred Hutch Cancer Center Study: ROR1 CAR T Cells in Peripheral Blood Samples Demonstrated Increased Markers of Exhaustion in Patients with Solid Tumors Compared to Those with Chronic Lymphocytic Leukemia (CLL) Solid Tumors: Cells Exhaust CLL: Cells Did Not Exhaust CD4 CD8 CD4 CD8 (n=2) (n=3) TIGIT LAG3 TIGIT LAG3 No elevation of Elevation of exhaustion markers exhaustion markers Clinical Outcome: Response in 2/2 patients Clinical Outcome: Response in 0/14 patients with single dose • 1 partial response • 1 partial response after re-treatment • 1 complete response Riddell et al, Keystone, 2020 5 ©2024 Lyell Immunopharma, Inc. CAR, chimeric antigen receptor; ROR1, receptor tyrosine kinase-like orphan receptor 1 Mean-fold increase in % Mean-fold increase in % positive cells positive cells Mean-fold increase in % positive cells Mean-fold increase in % positive cells
LYL797 was Designed to Overcome Two Key Barriers to Cell Therapy in Solid Tumors: Lack of T-cell Expansion and Rapid T-cell Exhaustion Lack of durable stemness and cell death Proliferation & cell differentiation Tumor antigen Tumor cell Repeat antigen stimulation T-cell exhaustion – 6 ©2024 Lyell Immunopharma, Inc.
LYL797: Improved Tumor Control and Prolonged Survival In Vivo NSCLC (H1975) Xenograft Model LYL797 Reduced Tumor Burden LYL797 Prolonged Survival 6 6 5 x 10 CAR T cells 5 x 10 CAR T cells Genetic Epigenetic Reprogramming Reprogramming c-Jun regulates the Manufacturing protocol AP-1 transcription that is designed to factor pathway, which generate more plays a key role in stem-like cells that self Days after T Cell Injection Days after T Cell Injection T-cell effector function renew and persist despite and resistance to T-cell repeat antigen stimulation Mock Control ROR1 CAR T LYL797 exhaustion Park et al., ASGCT, 2022 *P<0.05, ***P<0.001, ****P<0.0001 AP-1, Activator Protein-1; CAR, chimeric antigen receptor; NSCLC, non-small cell lung cancer; ROR1, receptor tyrosine kinase-like orphan receptor 1 7 ©2024 Lyell Immunopharma, Inc. 3 Tumor Volume (mm ) % Survival
LYL797: Phase 1 Trial Design Patient Population mTPI-2 Dose Escalation Followed by Dose Expansion • Patients with relapsed/refractory TNBC after failure of at least two Dose Escalation Dose Expansion lines of therapy • Patients with relapsed/refractory Dose Level 4 NSCLC after failure of at least one TNBC line of therapy (N~15) RP2D • ROR1 positive tumors Dose Level 3 NSCLC Study Objectives (N~15) • Safety and tolerability Dose Level 2 • Objective response rate and durability Dose Level 1 • Recommended Phase 2 dose • CAR T-cell pharmacokinetics De-escalation if required • Assessment of T-cell phenotype Lymphodepletion regimen: 3 days Dose Level -1 2 and infiltration Cyclophosphamide, 500 mg/m /day 2 Fludarabine, 30 mg/m /day NCT05274451; CAR, chimeric antigen receptor; m-TPI-2, Modified Toxicity Probability Interval; NSCLC, non-small cell lung cancer; ROR1, 8 ©2024 Lyell Immunopharma, Inc. receptor tyrosine kinase-like orphan receptor 1; RP2D, recommended phase 2 dose; TNBC, triple-negative breast cancer
LYL797: Updated Dose Escalation Design Dose Escalation (mTPI-2) Dose Expansion • No dose-limiting toxicities in patients without lung metastases 6 450 x 10 cells • Pneumonitis observed in some patients with lung metastases TNBC RP2D (N~15) ⎼ Separately escalating cohorts of 6 300 x 10 cells patients based on lung involvement NSCLC ⎼ Dexamethasone prophylaxis for all With lung 6 (N~15) 150 x 10 cells involvement patients 6 100 x 10 cells • Dexamethasone prophylaxis regimen intended to enable dose expansion regardless of lung involvement 6 75 x 10 cells 6 50 x 10 cells Lymphodepletion regimen: 3 days 2 Cyclophosphamide, 500 mg/m /day 2 Fludarabine, 30 mg/m /day Data cutoff of 29 May 2024; NCT05274451 m-TPI-2, Modified Toxicity Probability Interval; NSCLC, non-small cell lung cancer; RP2D, recommended phase 2 dose; TNBC, triple- 9 ©2024 Lyell Immunopharma, Inc. negative breast cancer
LYL797 Clinical Data Update David R. Spigel, MD Chief Scientific Officer Sarah Cannon Research Institute Nashville, TN
Patient Characteristics Predominantly TNBC with Multiple Lines of Prior Therapy 6 6 6 6 6 50 x 10 cells 75 x 10 cells 100 x 10 cells 150 x 10 cells 300 x 10 cells Total n = 8 n = 2 n = 4 n = 5 n = 1 N = 20 Age, mean 54 59 48 48 58 52 Indication, n (%) TNBC 6 (75%) 1 (50%) 3 (75%) 5 (100%) 1 (100%) 16 (80%) NSCLC 2 (25%) 1 (50%) 1 (25%) 0 0 4 (20%) Prior lines of treatment*, mean 5 (3 – 9) 8 (4 – 12) 5 (4 – 7) 5 (2 – 8) 8 6 (2 – 12) (range) ECOG at Screening, n (%) 0 3 (38%) 1 (50%) 2 (50%) 3 (60%) 1 (100%) 10 (50%) 1 5 (62%) 1 (50%) 2 (50%) 2 (40%) 0 10 (50%) *In the metastatic setting; Data Cutoff of 14 June 2024 ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer, TNBC, triple-negative breast cancer 11 ©2024 Lyell Immunopharma, Inc.
Dose-Dependent Clinical Activity with 40% Objective Response Rate at Highest Completed Dose Level 6 6 6 6 Efficacy evaluable 50 x 10 cells 100 x 10 cells 150 x 10 cells 300 x 10 cells Total patients, n n = 6 n = 4 n = 5* n = 1 N = 16 Patients with CR/PR, n 0 0 2 0 2 Patients with SD, n 1 1 1 1 4 ORR % 0% 0% 40% 0% 13% Duration of Response 2 cPRs to Day 90 Clinical Benefit Rate 17% 25% 60% 100% 38% * 5 patients with TNBC; Data cutoff of 29 May 2024 cPR, confirmed partial response; CR, complete response; ORR, objective response rate; PR, partial response; SD, stable disease 12 ©2024 Lyell Immunopharma, Inc.
Best Response for Target Lesions Demonstrating Clinical Activity 50M cells 100M cells 150M cells 300M cells Change from Baseline (%) Individual Patients 13 ©2024 Lyell Immunopharma, Inc. Data cutoff of 29 May 2024
Clinical Benefit Rate was Dose Dependent n = 1 • Clinical benefit rate is defined as SD, PR or CR as best response n = 5 n = 5 • Several patients had additional Clinical observations of clinical benefit Benefit Rate (%) including weight gain, decreased pain and improved n = 4 n = 4 liver function tests n = 6 50M cells 100M cells 150M cells 300M cells Dose Level Data cutoff of 29 May 2024 14 ©2024 Lyell Immunopharma, Inc. CR, complete response, DL, dose level; PR, partial response, SD, stable disease
Treatment Related Adverse Events: All Dose-Limiting Toxicities in Patients with Lung Involvement and Prior to Implementing Dexamethasone Prophylaxis 6 6 6 6 6 Safety Evaluable 50 x 10 cells 75 x 10 cells 100 x 10 cells 150 x 10 cells 300 x 10 cells Patients With: n = 7 n = 1 n = 4 n = 5 n = 1 TRAEs Grade > 3 2 0 2 3 0 DLTs 0 0 2 2 0 (pneumonitis, hypoxia) CRS 4 (G1, 2) 0 3 (G1, 2) 3 (G1, 2) 1 (G1) ICANS 0 0 0 0 0 • The most frequently reported related adverse events of any grade were CRS, pneumonitis and headache, and the expected cytopenia from lymphodepletion • CRS was generally mild (Grade 1 or 2), characterized by fever, and treated with tocilizumab and steroids • The most frequently reported Grade > 3 related adverse events were pneumonitis and hypoxia, and the expected cytopenia from lymphodepletion; the first patient with pneumonitis had acute Grade 5 respiratory failure on Day 41. Subsequently, all patients were treated early for any sign of pneumonitis Data cutoff of 29 May 2024; CRS, cytokine release syndrome; DLT, dose-limiting toxicity; ICANS, immune-effector cell-associated 15 ©2024 Lyell Immunopharma, Inc. neurotoxicity syndrome; TRAE, treatment-related adverse event
Pneumonitis has a Predictable Onset and is Treatable • Pneumonitis does not appear to be related to on-target, off-tumor toxicity; we believe it is related to local cytokine production due to underlying lung disease • The onset is predictable(generally 4 – 10 days after treatment) • It has been effectively treated with early high-dose steroids • All patients now treated prophylactically with dexamethasone – Dexamethasone use has resulted in decreased CRS without diminished efficacy in hematological malignancies and CD19 CAR therapy* • Dose escalation is moving forward separately in patients with or without NSCLC or lung metastatic disease 6 – Dosing at 300 x 10 cells for patients without lung involvement 6 – Dosing at 75 x 10 cells for patients with lung involvement Data cutoff of 29 May 2024 CAR, chimeric antigen receptor; CRS, cytokine release syndrome; NSCLC, non-small cell lung cancer 16 ©2024 Lyell Immunopharma, Inc. *Oluwole, OO, et al, Bone Marrow Transplant, 59, 2024
Case Report of LYL797 Clinical Activity Patient with metastatic triple-negative breast cancer with confirmed partial response following LYL797 after having failed 3 prior lines of treatment % Change from Screening to Baseline 51-year-old female previously treated with Best % Change from Baseline (1) doxorubicin, cyclophosphamide, pembrolizumab, paclitaxel and carboplatin, (2) capecitabine and (3) doxorubicin before enrolling in LYL797 trial with enlarging pelvic mass. 6 Treated with 150 x 10 LYL797 CAR T cells. Pelvic mass decreased in size from 17.6 cm at baseline to 11.4 cm at Day 60. Data cutoff of 29 May 2024, Patient 5 17 ©2024 Lyell Immunopharma, Inc. CAR, chimeric antigen receptor; CT, computed tomography % Change in Sum of Diameters
Case Report of LYL797 Clinical Activity Patient with metastatic non-small cell lung cancer with stable disease for 6 4 months following LYL797 at a dose of 50 x 10 cells • 49-year-old male diagnosed with metastatic NSCLC and treated with XRT then (1) carbo/pemetrexed and pembrolizumab, (2) a novel IL-2, additional XRT for rib metastasis and 2 RUL lesions, (3) taxotere/ramucirumab prior to LYL797 • No CRS after LYL797 infusion; no > G3 events other than cytopenia • Patient’s rapidly growing right upper lobe lesion had doubled in the 3 months prior to treatment, growing from 1.4 to 3.1 cm in longest diameter, then remained stable until progression four months after treatment • During that time patient experienced weight gain, improved sleep and quality of life Data cutoff of 29 May 2024 , Patient 17 CRS, cytokine release syndrome; NSCLC, non-small cell lung cancer; XRT, radiation therapy 18 ©2024 Lyell Immunopharma, Inc.
Confirmed Partial Responses in Patients Who had Progression in their Target Lesions Between Screening and Baseline % Change from Screening to Baseline % Change from Screening to Baseline Best % Change from Baseline Best % Change from Baseline % Change in % Change in Sum of Sum of Diameters Diameters Patient 5 Patient 8 6 6 (150 x 10 cells) (150 x 10 cells) 19 ©2024 Lyell Immunopharma, Inc. Data cutoff of 29 May 2024
LYL797 Translational Science Gary Lee, PhD Chief Scientific Officer
LYL797 Translational Data: Key Findings Expansion • LYL797 CAR T-cell expansion observed in the peripheral blood from all patients (n=11) CAR T Cell Phenotype • LYL797 cells had low exhaustion markers and a significant proportion of cells with the desired stem-like and effector-memory phenotype (n=6) Infiltration and Tumor Lysis • Persistent LYL797 CAR T cell infiltration present in all evaluable on-study tumor biopsies (n=9) with histologic evidence of tumor lysis in some samples Data cutoff of 29 May 2024 CAR, chimeric antigen receptor 21 ©2024 Lyell Immunopharma, Inc.
LYL797 CAR T-cell Expansion Observed in Peripheral Blood Samples from All Treated Patients Peak Expansion Between Days 8 and 11 100000 6 DL 1 50 x 10 cells (n = 5) DL 1 DL 1A 6 100 x 10 cells (n = 1) DL 1A DL 2 Median Peak PK 10000 6 DL 2 150 x 10 cells (n = 5) 1000 Median peak PK = 11,251 copies/µg DNA 100 6 LLOQ • 50 x 10 : 4,783 copies/µg DNA 6 • 150 x 10 : 15,598 copies/µg DNA 10 1 0.1 0 20 40 60 80 100 Relative Day from LYL797 Infusion Days Post LYL797 Infusion 22 ©2024 Lyell Immunopharma, Inc. Data cutoff of 29 May 2024; CAR, chimeric antigen receptor; cPR, confirmed partial response; PK, pharmacokinetics; DNA, deoxyribonucleic acid LYL797 copies/ug DNA LYL797 copies/µg DNA
Infusion Products and LYL797 in Day 11 Peripheral Blood Samples Had Significantly Lower Percent TIGIT+ Cells (Exhaustion Marker) Fred Hutch Cancer Center: Solid Tumor Patients LYL797 CAR T Cell Data 100 100 100 80 80 80 60 60 60 + + + % TIGIT % TIGIT % TIGIT 40 CAR T cells CAR T cells CAR T cells 40 40 20 20 20 0 n = 4 0 0 Product Peak Product Day 11 Product Data cutoff of 29 May 2024; CAR, chimeric antigen receptor; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domain Specht J. Jan 31 2020, EHA 23 ©2024 Lyell Immunopharma, Inc. *LYL797 defined by CD8+ EGFR+
LYL797 Cells Had an Exhaustion Profile More Comparable to Published Data from CD19 CAR PBMC Samples than Exhausted TNBC TIL Samples mRNA by RNAseq/ transcriptomic analyses Exhaustion related gene set consistent among multiple tumor types (N = 18 genes) LYL797 PublicStudy1 PublicStudy2 Exhausted TILs LYL797: EGFR+CD8+ cells from Day11 PBMC Exhaustion Enrichment PublicStudy1: CD8 CAR-T cells from PBMC at expansion Score peak of CD19 CAR-T in Sheih, A. et al., Nat Commun 2020 PublicStudy2: CD8 CAR-T cells from PBMC at expansion peak of CD19 CAR-T in Mercedes Guerrero-Murillo, et al., bioRxiv, 2024 Exhausted TILs: refer to the t_CD8_CXCL13 cluster from TNBC samples in Zhang, et al., Cancer Cell. 2021. Only patients with at least 300 cells in the t_CD8_CXCL13 cluster were included in the comparison Exhaustion enrichment score is average of enrichment score calculated by UCell across all cells Data cutoff of 29 May 2024; Zhang et al., Nature 2018 CAR, chimeric antigen receptor; mRNA, messenger RNAseq, RNA sequencing; PBMC, 24 peripheral blood mononuclear cells; TIL, tumor infiltrating lymphocytes ©2024 Lyell Immunopharma, Inc. LYL797 CD19 CAR T Exhausted TILs
LYL797 Cells from Day 11 and Day 22 PBMC Samples Had a Significant Proportion of Cells with Stem-like and Effector-memory Phenotype * mRNA by RNAseq/ transcriptomic analyses LYL797 Compared to CD19 CAR * LYL797 from Day 11 PBMC Samples Stem-like Phenotype Stem-like Effector memory Stem-like Effector-like Effector memory Effector memory Effector-like Effector-like On-study On-study PBMC Samples PBMC Samples umap_1 Data cutoff of 29 May 2024; *LYL797 defined by CD8+ EGFR+ 25 ©2024 Lyell Immunopharma, Inc. PBMC, peripheral blood mononuclear cells; mRNA, messenger RNAseq, RNA sequencing; CAR, chimeric antigen receptor umap_2 % in LYL797* % in CD19 CAR*
Detection of LYL797 CAR T Cell Infiltration in All Evaluable (N=9) On-study Tumor Biopsies (Days 21-30) In situ detection of CAR-specific T cells using anti-ROR1 scFv mRNA in situ hybridization (ISH) assay T cell receptor ROR1 CAR T Nucleus 6 Data cutoff of 29 May 2024; Patient 18; TNBC; 100 x 10 cells; Day 29 tumor biopsy of abdominal mass CAR, chimeric antigen receptor; H&E: Hematoxylin & Eosin; mISH: multiplex fluorescent in situ hybridization; mRNA, messenger RNA; 26 ©2024 Lyell Immunopharma, Inc. ROR1, receptor tyrosine kinase-like orphan receptor 1
LYL797 CAR T Cell Infiltration in Patient with Confirmed Partial Response (Patient 8) T cell receptor ROR1 CAR T Nucleus 6 Data cutoff of 29 May 2024; Patient 8; TNBC; 150 x 10 cells; Day 28 tumor biopsy of lung CAR, chimeric antigen receptor; H&E: Hematoxylin & Eosin; mISH: multiplex fluorescent in situ hybridization; ROR1, receptor tyrosine 27 ©2024 Lyell Immunopharma, Inc. kinase-like orphan receptor 1
Persistent LYL797 CAR T Cell Infiltration Observed in Tumor Sample >4 months Post-infusion (Patient 8) Lymph node resected at time of surgery with no evidence of disease T cell receptor ROR1 CAR T Nucleus 6 Data cutoff of 29 May 2024; Patient 8; TNBC; 150 x 10 cells; 2nd post-LYL797 infusion tumor biopsy on Day 126 CAR, chimeric antigen receptor; H&E: Hematoxylin & Eosin; mISH: multiplex fluorescent in situ hybridization; ROR1, receptor tyrosine 28 ©2024 Lyell Immunopharma, Inc. kinase-like orphan receptor 1
Multiple Tumor Biopsies Had Features Consistent with T Cell-mediated Tumor Lysis Including T Cell-rich Inflammation with Scattered Tumor Cells Scattered tumor cells with lymphocytic cells Fibrous stroma Patient 3, TNBC Patient 5, TNBC Patient 8, TNBC 6 6 50 x 10 cells, Day 26 liver biopsy 6 150 x 10 cells, Day 23 liver biopsy 150 x 10 cells, Day 28 lung biopsy Data cutoff of 29 May 2024 29 ©2024 Lyell Immunopharma, Inc. H&E: Hematoxylin & Eosin; TNBC, triple-negative breast cancer
LYL797 Data Summary LYL797 CAR T cells had dose-dependent clinical activity and expanded, infiltrated, persisted and killed tumor cells in patients with TNBC ü 40% ORR and 60% CBR at 150M cells; dose escalation continuing ü No significant safety signal related to LYL797 observed in patients without lung involvement; steroid prophylaxis to mitigate pneumonitis in patients with lung involvement ü Persistent LYL797 CAR T cell infiltration (up to 4 months) present in all evaluable on-study tumor biopsies with histologic evidence of tumor lysis in some samples ü CAR T cell expansion observed in the peripheral blood, with low inhibitory markers of exhaustion and a significant proportion of cells with the desired stem-like and effector-memory phenotype ü Clinical data validate preclinical models that demonstrate benefit of LYL797 over ROR1 CAR T cells without c-Jun and Epi-R ü Translational and early clinical data validate hypothesis that c-Jun overexpression and Epi-R technologies can improve clinical benefit of LYL797 ROR1 CAR T cell activity ü 100% manufacturing success rate to date Data cutoff of 29 May 2024; CAR, chimeric antigen receptor; CBR, clinical benefit rate; ORR, objective response rate; ROR1, receptor tyrosine 30 ©2024 Lyell Immunopharma, Inc. kinase-like orphan receptor 1; TNBC, triple-negative breast cancer
Next Steps for ROR1 CAR T Cell Program Demonstrated clinical activity supports expanded development of LYL797 and LYL119 LYL797 • Select Recommended Phase 2 Dose for LYL797 expansion cohort(s) • Generate data at higher dose levels expected to achieve more durable responses • Dose escalate with steroid prophylaxis in patients with lung involvement • Enroll patients with platinum-resistant ovarian and endometrial cancers in addition to TNBC and NSCLC • Initiate a study in hematologic malignancies including multiple myeloma and CLL LYL119 • IND submitted and awaiting clearance • Protocol includes enrollment of patients with platinum-resistant ovarian, endometrial, NSCLC, TNBC and colorectal cancers CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; IND, investigational new drug application; NSCLC, non-small cell 31 ©2024 Lyell Immunopharma, Inc. lung cancer; TNBC, triple-negative breast cancer
LYL119: Incorporates Novel Stackable Technologies Designed to Improve Potency Anti-ROR1 CAR ™ c-Jun Epi-R Overexpression Patient LYL119 T cells ™ NR4A3 Stim-R Knockout Tumor cells CAR, chimeric antigen receptor; NR4A3, The nuclear receptor 4A3; ROR1, receptor tyrosine kinase-like orphan receptor 1 32 ©2024 Lyell Immunopharma, Inc. NR4A3 knockout with CRISPR/Cas9
LYL119, Next-generation ROR1-targeted CAR T, Demonstrated More Potent Anti-tumor Activity In Vivo Significantly Improved Elimination of Significantly Improved Animal Xenograft Tumors at the Lower Survival at the Lower 6 6 0.1 x 10 CAR T-cell Dose 0.1 x 10 CAR T-cell Dose 6 1 x 10 CAR T cells 6 0.1 x 10 CAR T cells Days After T Cell Injection Days After T Cell Injection 6 - -- PBS Mock non-transduced (Epi-R + Stim-R) 1.42 x 10 cells LYL797 (non-edited + c-Jun + Epi-R) LYL119 (NR4A3 KO + c-Jun + Epi-R + Stim-R) *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 33 ©2024 Lyell Immunopharma, Inc. PBS, phosphate buffered saline; CAR, chimeric antigen receptor; ROR1, receptor tyrosine kinase-like orphan receptor 1 Tumor Volume Tumor Volume 3 3 (mm ) (mm ) % Survival % Survival
ROR1 is Highly Expressed in Many Malignancies Expression associated with a poor prognosis in solid tumors Solid Tumor Indications in Development TNBC NSCLC Endometrial Ovarian ROR1 Expression 51%* 35%* ~50% ~50% ~40K new cases ~200K new cases ~68K new cases ~20K new cases US Incidences ~10K deaths ~110K deaths ~13K deaths ~13K deaths Hematologic Indications in Development Multiple CLL Myeloma ROR1 Expression ~60% ~95% ~36K new cases ~ 21K new cases US Incidences ~13K deaths ~ 4.4K deaths *Data from Lyell’s LYL797 clinical trial (TNBC N=259, NSCLC, N=104) CLL, chronic lymphocytic leukemia; NSCLC, non-small cell lung cancer; TNBC, triple-negative breast cancer American Cancer Society (cancer.org); Balakrishnan et al., Clin Cancer Res 2017; Liu et al., Sci Reports, 2020; 34 ©2024 Lyell Immunopharma, Inc. Mosaad et al., Asian Pac J Cancer Prev, 2023; Zhang et al., Am J Pathol, 2012.; Daneshmanesh, et al., Leuk Lymphoma, 2013
Upcoming Potential Milestones Balance sheet of $526M* provides cash runway into 2027, through multiple clinical milestones LYL797 ROR1 CAR T cell + c-Jun + Epi-R q Begin enrolling patients with ovarian or endometrial cancers q Submit IND for trial in patients with multiple myeloma or CLL 2H24 q Clinical data update including initiation of dose expansion (late-2024/early-2025) 1H25q Present updated Phase 1 data at a major medical conference LYL119 ROR1 CAR T cell + c-Jun + NR4A3 CRISPR Knockout + Epi-R + Stim-R 2H24q IND clearance 1H25q Progress update on Phase 1 trial 2H25q Initial clinical data LYL845 TIL + Epi-R 2H24q Initial clinical data in patients with advanced melanoma *Cash, cash equivalents and marketable securities as of 3/31/2024 CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; IND, investigational new drug application; NR4A3, nuclear 35 ©2024 Lyell Immunopharma, Inc. receptor 4A; ROR1, receptor tyrosine kinase-like orphan receptor 1; TIL, tumor-infiltrating lymphocytes
With Thanks Our gratitude to patients, caregivers, investigators, clinical site teams and Lyell employees for their contributions to advance innovative cell therapies to people with cancer 36 ©2024 Lyell Immunopharma, Inc.
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