c-Jun

Reported dose-dependent antitumor clinical activity in patients with relapsed/refractory triple-negative breast cancer from the Phase 1 trial of LYL797, a ROR1-targeted Chimeric Antigen Receptor (CAR) T‑cell product candidate enhanced with proprietary anti-exhaustion technology; 40% objective response rate and 60% clinical benefit rate at the highest dose cleared at the time of the initial data report (150 x 106 CAR T cells)Expanded development of LYL797 into four new tumor types, including ROR1+ relapsed/refractory platinum‑resistant ovarian cancer, endometrial cancer, multiple myeloma and chronic lymphocytic leukemiaReceived FDA clearance of an IND for LYL119, a next-generation ROR1-targeted CAR T-cell product candidate incorporating four proprietary technologies designed to enhance the anti-exhaustion capability and persistence of T cellsCash, cash equivalents and marketable securities of $491.1 million as of June 30, 2024 supports advancing diverse pipeline through multiple clinical milestones into 2027 SOUTH SAN FRANCISCO, Calif., Aug. 07, 2024 (GLOBE NEWSWIRE) -- Lyell Immunopharma, Inc. (Nasdaq: LYEL), a clinical‑stage T-cell reprogramming company advancing a diverse pipeline of cell therapies for patients with solid tumors or hematologic malignancies, today reported financial results and business highlights for the second quarter ended June 30, 2024. “We are pleased that initial data from our Phase 1 trial of LYL797 demonstrated dose-dependent clinical activity and that LYL797 CAR T cells expanded, infiltrated solid tumors and killed cancer cells in patients. Based on these promising initial data, we have expanded the cancer indications under evaluation in this trial to include patients with ovarian and endometrial cancers, and we plan to file an IND to initiate a new trial evaluating LYL797 in multiple myeloma and chronic lymphocytic leukemia,” said Lynn Seely, M.D., Lyell’s President and CEO. “In addition, our IND for LYL119, a next generation ROR1-targeted CAR T‑cell product candidate designed with four technologies to generate T cells with even greater capacity to resist exhaustion, has been cleared by the FDA, and we expect to report initial clinical data from the Phase 1 trial in the second half of 2025. We remain on track to report initial clinical data from our lead TIL program in the second half of this year. Our strong cash position enables us to advance multiple product candidates through critical clinical milestones and fund operations into 2027.” Second Quarter Updates and Recent Business Highlights Lyell is advancing four wholly-owned product candidates. Two product candidates, LYL797 and LYL845, are in Phase 1 clinical development, and LYL119 is entering Phase 1 clinical development. A second-generation tumor infiltrating lymphocyte (TIL) product candidate is in preclinical development. LYL797 – A ROR1-targeted CAR T-cell product candidate enhanced with anti-exhaustion technology designed for improved tumor infiltration and tumor cell killing Enrollment in the Phase 1 clinical trial of LYL797 is ongoing. The study was initiated in patients with relapsed/refractory triple-negative breast cancer (TNBC) or non-small cell lung cancer (NSCLC). Based on the initial clinical data that demonstrated dose-dependent anti-tumor activity, the trial has been expanded to include patients with platinum-resistant ovarian or endometrial cancers and an investigational new drug (IND) application is expected to be submitted in the second half of this year to initiate a second Phase 1 clinical trial of LYL797 in multiple myeloma and chronic lymphocytic leukemia (CLL).Initial clinical and translational data from the Phase 1 clinical trial of LYL797 were reported in June 2024. The initial dataset of 20 patients (16 patients with TNBC and four patients with NSCLC) 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 a 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 at the time data were reported. Common treatment-related adverse events (TRAE) 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 some patients with lung metastases, including the index patient who experienced Grade 5 respiratory failure on Day 41. All patients are now given dexamethasone prophylaxis and dose escalation is continuing separately and more gradually in patients with lung involvement. No dose‑limiting toxicities have been reported in patients without lung involvement.Updated data from the ongoing Phase 1 trial in solid tumor indications, including the initiation of dose expansion, are expected in late 2024 – early 2025. LYL845 – A TIL product candidate epigenetically reprogrammed using Lyell’s proprietary Epi-R manufacturing protocol, designed for differentiated potency and durability Enrollment in the Phase 1 clinical trial of LYL845 is ongoing. The trial is designed to include patients with relapsed or refractory metastatic or locally advanced melanoma, NSCLC and colorectal cancer.Initial clinical and translational data from the Phase 1 trial of LYL845 in patients with advanced melanoma are expected in the second half of 2024. LYL119 – A next-generation ROR1-targeted CAR T-cell product candidate incorporating four stackable and complementary anti-exhaustion technologies designed for enhanced potency LYL119 is a ROR1-targeted CAR T-cell product enhanced with four novel genetic and epigenetic reprogramming technologies: c-Jun overexpression, NR4A3 knockout, Epi-R manufacturing protocol and Stim‑RTM T-cell activation technology.An IND application for LYL119 has received clearance from the U.S. Food and Drug Administration (FDA).The Phase 1 trial is designed as an open‑label dose‑escalation and ‑expansion trial in patients with ROR1‑positive solid tumors and will initially enroll patients with ROR1‑positive platinum‑resistant ovarian cancer or endometrial cancer. It is estimated that approximately 50% of patients with ovarian cancer and approximately 50% of patients with endometrial cancer have ROR1‑positive tumors.Initial clinical data are expected in the second half of 2025. Second Quarter Financial Results Lyell reported a net loss of $45.8 million for the second quarter ended June 30, 2024, compared to a net loss of $63.9 million for the same period in 2023. Non‑GAAP net loss, which excludes non-cash stock-based compensation, non‑cash expenses related to the change in the estimated fair value of success payment liabilities and certain non-cash investment gains and charges, was $39.1 million for the second quarter ended June 30, 2024, compared to $45.6 million for the same period in 2023. GAAP and Non-GAAP Operating Expenses Research and development (R&D) expenses were $40.3 million for the second quarter ended June 30, 2024, compared to $47.5 million for the same period in 2023. The decrease in second quarter 2024 R&D expenses of $7.2 million was primarily driven by a decrease in personnel-related expenses associated with Lyell’s November 2023 reduction in workforce. Non‑GAAP R&D expenses, which exclude non-cash stock-based compensation and non-cash expenses related to the change in the estimated fair value of success payment liabilities for the second quarter ended June 30, 2024, were $37.2 million, compared to $41.6 million for the same period in 2023. The decrease in second quarter 2024 non-GAAP R&D expenses was primarily driven by a decrease in personnel-related expenses.General and administrative (G&A) expenses were $12.3 million for the second quarter ended June 30, 2024, compared to $19.0 million for the same period in 2023. The decrease in second quarter 2024 G&A expenses was primarily driven by decreases in non-cash stock-based compensation. Non‑GAAP G&A expenses, which exclude non-cash stock‑based compensation, for the second quarter ended June 30, 2024, were $7.8 million, compared to $10.1 million for the same period in 2023. The decrease in second quarter 2024 non-GAAP G&A expenses was primarily driven by a decrease in personnel-related expenses associated with Lyell’s November 2023 reduction in workforce. A discussion of non-GAAP financial measures, including reconciliations of the most comparable GAAP measures to non‑GAAP financial measures, is presented below under “Non-GAAP Financial Measures.” Cash, cash equivalents and marketable securities Cash, cash equivalents and marketable securities as of June 30, 2024, were $491.1 million, compared to $562.7 million as of December 31, 2023. Lyell believes that its cash, cash equivalents and marketable securities balances will be sufficient to meet working capital and capital expenditure needs into 2027. About Lyell Immunopharma, Inc. Lyell is a clinical-stage T-cell reprogramming company advancing a diverse pipeline of cell therapies, including three product candidates in or entering Phase 1 clinical development for patients with solid tumors or hematologic malignancies. Lyell’s product candidates are enhanced with novel anti-exhaustion technology 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 applies its proprietary ex vivo genetic and epigenetic reprogramming technology 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; 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 trial 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 anti-exhaustion technology to address barriers that limit consistent and long-lasting responses to cell therapy for solid tumors: T‑cell exhaustion and lack of durable stemness, and for its reprogramming technology to address these barriers to develop new medicines with improved durable clinical outcomes; Lyell’s anticipated progress, business plans, business strategy and clinical trials; Lyell’s advancement of its pipeline and its research, development and clinical capabilities; the potential clinical benefits and therapeutic potential of Lyell’s product candidates; the advancement of Lyell’s technology platform; Lyell’s expectation that its financial position and cash runway will support advancement of its pipeline through multiple clinical milestones into 2027; expectations around enrollment and the timing of initial and updated clinical and translational data from Lyell’s Phase 1 trials for LYL797, LYL845 and LYL119; 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: the effects of macroeconomic conditions, including any geopolitical instability and actual or perceived changes in interest rates and economic inflation; Lyell’s ability to submit planned INDs or initiate or progress clinical trials on the anticipated timelines, if at all; 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; the potential for results from clinical trials to differ from nonclinical, early clinical, preliminary or expected results; 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 June 30, 2024, being filed with the SEC today. 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. Lyell Immunopharma, Inc.Unaudited Selected Consolidated Financial Data(in thousands) Statement of Operations Data: Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Revenue$13 $27 $16 $92 Operating expenses: Research and development(1) 40,261 47,471 83,435 92,101 General and administrative 12,256 19,030 25,750 38,309 Other operating income, net (976) (569) (2,066) (1,857)Total operating expenses 51,541 65,932 107,119 128,553 Loss from operations (51,528) (65,905) (107,103) (128,461)Interest income, net 6,364 5,264 13,183 9,761 Other (expense) income, net (645) (326) 445 774 Impairment of other investments — (2,923) (13,001) (12,923)Total other income (loss), net 5,719 2,015 627 (2,388)Net loss$(45,809) $(63,890) $(106,476) $(130,849) (1)Lyell’s success payment liability was recognized at fair value as Fred Hutch had provided the requisite service obligation to earn the potential success payment consideration under the continued collaboration. The change in the estimated fair value of Fred Hutch success payment liabilities beginning in Q1 2023 was recognized within other (expense) income, net in the unaudited Condensed Consolidated Statements of Operations and Comprehensive Loss. The change in the estimated fair value of Stanford success payment liabilities was recognized within research and development expenses in the unaudited Condensed Consolidated Statements of Operations and Comprehensive Loss. Balance Sheet Data: As of June 30, 2024 As of December 31, 2023 Cash, cash equivalents and marketable securities$491,119 $562,729Property and equipment, net$93,096 $102,654Total assets$654,142 $750,029Total stockholders’ equity$566,501 $654,952 Non-GAAP Financial Measures To supplement our financial results and guidance presented in accordance with U.S. generally accepted accounting principles (GAAP), we present non-GAAP net loss, non-GAAP R&D expenses and non-GAAP G&A expenses. Non‑GAAP net loss and non-GAAP R&D expenses exclude non-cash stock-based compensation expense and non-cash expenses related to the change in the estimated fair value of success payment liabilities from GAAP net loss and GAAP R&D expenses. Non-GAAP net loss further adjusts non‑cash investment gains and charges, as applicable. Non‑GAAP G&A expenses exclude non-cash stock-based compensation expense from GAAP G&A expenses. We believe that these non-GAAP financial measures, when considered together with our financial information prepared in accordance with GAAP, can enhance investors’ and analysts’ ability to meaningfully compare our results from period to period, and to identify operating trends in our business. We have excluded stock-based compensation expense, changes in the estimated fair value of success payment liabilities and non-cash investment gains and charges from our non‑GAAP financial measures because they are non-cash gains and charges that may vary significantly from period to period as a result of changes not directly or immediately related to the operational performance for the periods presented. We also regularly use these non-GAAP financial measures internally to understand, manage and evaluate our business and to make operating decisions. These non-GAAP financial measures are in addition to, and not a substitute for or superior to, measures of financial performance prepared in accordance with GAAP. In addition, these non-GAAP financial measures have no standardized meaning prescribed by GAAP and are not prepared under any comprehensive set of accounting rules or principles and, therefore, have limits in their usefulness to investors. We encourage investors to carefully consider our results under GAAP, as well as our supplemental non-GAAP financial information, to more fully understand our business. Lyell Immunopharma, Inc.Unaudited Reconciliation of GAAP to Non-GAAP Net Loss(in thousands) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Net loss - GAAP$(45,809) $(63,890) $(106,476) $(130,849)Adjustments: Stock-based compensation expense 8,284 14,223 17,439 28,105 Impairment of other investments — 2,923 13,001 12,923 Change in the estimated fair value of success payment liabilities (1,534) 1,105 (566) (603)Net loss - Non-GAAP(1)$(39,059) $(45,639) $(76,602) $(90,424) (1)There was no income tax effect related to the adjustments made to calculate non-GAAP net loss because of the full valuation allowance on our net U.S. deferred tax assets for all periods presented. Lyell Immunopharma, Inc.Unaudited Reconciliation of GAAP to Non-GAAP Research and Development Expenses(in thousands) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Research and development - GAAP$40,261 $47,471 $83,435 $92,101 Adjustments: Stock-based compensation expense (3,865) (5,279) (7,657) (9,891)Change in the estimated fair value of success payment liabilities(1) 793 (605) 268 3 Research and development - Non-GAAP$37,189 $41,587 $76,046 $82,213 (1)Lyell’s success payment liability was recognized at fair value as Fred Hutch had provided the requisite service obligation to earn the potential success payment consideration under the continued collaboration. The change in the estimated fair value of Fred Hutch success payment liabilities beginning in Q1 2023 was recognized within other (expense) income, net in the unaudited Condensed Consolidated Statements of Operations and Comprehensive Loss. The change in the estimated fair value of Stanford success payment liabilities was recognized within research and development expenses in the unaudited Condensed Consolidated Statements of Operations and Comprehensive Loss. Lyell Immunopharma, Inc.Unaudited Reconciliation of GAAP to Non-GAAP General and Administrative Expenses(in thousands) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 General and administrative - GAAP$12,256 $19,030 $25,750 $38,309 Adjustments: Stock-based compensation expense (4,419) (8,944) (9,782) (18,214)General and administrative - Non-GAAP$7,837 $10,086 $15,968 $20,095 Contact:Ellen RoseSenior Vice President, Communications and Investor Relationserose@lyell.com

Shares in Lyell Immunopharma plummeted 35% on Wednesday after the company revealed that, despite showing promise in solid tumours, a Phase I trial of its experimental CAR-T therapy LYL797 faces safety challenges, particularly in patients with lung involvement."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," commented David Spigel, a lead investigator in the study.LYL797 is a ROR1-targeted CAR T-cell therapy that uses Lyell's genetic and epigenetic reprogramming tools to prevent T cells from becoming exhausted. The treatment works by overexpressing a protein called c-Jun to correct for an imbalance in the AP-1 family of transcription factors present in exhausted T cells.The initial dataset of 20 treated patients in the study includes 16 with triple-negative breast cancer (TNBC) and four with non-small-cell lung cancer (NSCLC). All had relapsed/refractory metastatic disease. Four dose levels have been explored to date.Case of fatal respiratory failure The most common Grade ≥3 side effects were pneumonitis (17%) and hypoxia (11%), along with expected cytopenia due to lymphodepletion (78%). There were no reports of immune effector cell-associated neurotoxicity syndrome (ICANS) attributed to LYL797.One patient died from respiratory failure on day 41. According to Lyell, Grade ≥3 pneumonitis occurred only in patients with TNBC and lung metastases, prompting the company to separate dose escalation into two cohorts based on lung involvement. Patients without lung involvement are currently being evaluated at the 300 x 106 cell dose level, which is the highest dose level, while those with lung metastases, primary lung tumours, or pleural effusion are being treated more cautiously at the 75 x 106 cell dose level.ORR of 40%Despite the setbacks, the trial showed some promising efficacy signals. Among the five patients with TNBC treated at the 150 x 106 cell dose level, two had confirmed partial responses to day 90, resulting in an objective response rate (ORR) of 40%. The clinical benefit rate (CBR) was 60% at the 150 x 106 cell dose level, and 38% across all dose levels"We are encouraged to see clinical responses and a clear dose-dependent indication of anti-tumour clinical activity … in patients with advanced triple-negative breast cancer," said CEO Lynn Seely. "Our translational data provide, to our knowledge, the first demonstration of persistent CAR T cell infiltration into solid tumours associated with evidence of cancer cell killing."LYL797 CAR T-cells increased in number in blood samples by day 60 for all 11 patients studied so far, with peak expansion happening between days 8 and 11. Those who received 150 x 106 cells had three times more CAR T-cells at their peak than those who received 50 x 106 cells. Further, only a "low proportion" CAR T-cells showed the exhaustion marker TIGIT by day 11, which Lyell says supports c-Jun overexpression as a way of preventing cell exhaustion."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… and also to initiate a new clinical trial for patients with multiple myeloma and chronic lymphocytic leukaemia," Seely said. She added that Lyell plans to move its next-generation ROR1-targeted product LYL119, developed with "even more powerful anti-exhaustion technology," into the clinic later this year.

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 (GLOBE NEWSWIRE) -- 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 . 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