Abstract 777TiP
Background
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of B-cell malignancies, but efficacy in solid tumors is lacking due to barriers such as T-cell exhaustion and lack of durable stemness. We have developed ex vivo genetic and epigenetic T-cell reprogramming technologies to address these barriers: Gen-R™ to overcome exhaustion and Epi-R™ to improve stemness. LYL797 is an autologous ROR1-targeted CAR T-cell product incorporating Gen-R and Epi-R technologies in development to treat relapsed and/or refractory, ROR1+ triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Preclinical studies in ROR1+ TNBC and NSCLC tumor models demonstrate improved functional activity compared to ROR1-targeted CAR T cells without Gen-R and Epi-R modifications.
Trial design
LYL797-101 is a phase 1, first-in-human, multicenter, single-arm, open label, dose-escalation and -expansion study to evaluate the safety, pharmacokinetics (PK), and anti-tumor activity of LYL797 in ROR1+ TNBC and NSCLC. The study will enroll up to 54 adult patients (pts) with locally advanced or metastatic, unresectable ROR1+ (by central laboratory) TNBC or NSCLC. Pts must have received at least two prior lines of systemic therapy, including a taxane (TNBC) or checkpoint inhibitor(s) (NSCLC); have ECOG status 0-1; and life expectancy ≥ 3 months; pts with treated, stable, asymptomatic brain metastases are eligible. The dose escalation phase has 4 planned dose levels and will enroll TNBC pts using an mTPI-2 design with a 28-day dose-limiting toxicity monitoring period. Dose escalation will continue until a recommended phase 2 dose (RP2D) is determined; dose-expansion is designed to enroll 15 TNBC and 15 NSCLC pts at the RP2D. After leukapheresis and manufacturing, pts receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by LYL797 infusion at the protocol-assigned dose level. Primary objectives include LYL797 RP2D determination and safety and tolerability; secondary objectives include anti-tumor activity and PK. The trial began screening in March 2022.
Clinical trial identification
NCT05274451.
Editorial acknowledgement
Lori K. Pender, PharmD, MPH from Lyell Immunopharma.
Legal entity responsible for the study
Lyell Immunopharma.
Funding
Lyell Immunopharma.
Disclosure
D.R. Spigel: Financial Interests, Institutional, Principal Investigator: Lyell Immunopharma. H. Murthy: Financial Interests, Institutional, Advisory Board: CRISPR Therapeutics; Financial Interests, Institutional, Research Grant: CRISPR Therapeutics; Financial Interests, Institutional, Principal Investigator: Lyell Immunopharma. S. Chumsri: Financial Interests, Institutional, Principal Investigator: Lyell Immunopharma. B.J. Ganguly: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma; Financial Interests, Personal, Stocks/Shares: Lyell Immunopharma. L. Gong: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma. H. Hiraragi: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma; Financial Interests, Personal, Stocks/Shares: Lyell Immunopharma. E. Larsen: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma. W. Liu: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma; Financial Interests, Personal, Stocks/Shares: Lyell Immunopharma. L. Martell: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma. S. Zhu: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma; Financial Interests, Personal, Stocks/Shares: Lyell Immunopharma. I. Bornman: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma. S. Fitzsimmons: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma. E. Barnum: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma. S. Christiansen: Financial Interests, Personal, Full or part-time Employment: Lyell Immunpharma. H. Gillenwater: Financial Interests, Personal, Full or part-time Employment: Lyell Immunopharma.