Phase 1 Clinical Trial Will Assess CAR-T With Genetic and Epigenetic Reprogramming for Solid Tumors

Plans for a phase 1 clinical trial (NCT05274451) for LYL797, an autologous investigational ROR1-targeted chimeric antigen receptor (CAR) T-cell therapy, which has begun screening patients, were detailed in a poster exhibited at the European Society for Medical Oncology (ESMO) 2022 Congress, September 9-13, 2022 in Paris, France.¹

LYL797 incorporates Gen-R technology, which is a form of genetic reprogramming intended to overcome T-cell exhaustion, and Epi-R technology, a form of epigenetic reprogramming which is intended to generate T-cells with properties of durable stemness via an optimized manufacturing process. It is under investigation for the treatment of relapsed/refractory (r/r) triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Improved functional activity compared to ROR-1-targeted CAR-T therapies without the 2 forms of reprogramming was demonstrated in preclinical studies in models of ROR1+ TNBC and NSCLC tumors. LYL797 is being developed by Lyell Immunopharma, which announced the FDA’s clearance of its investigational new drug (IND) application for the therapy late last year.²

“While CAR T-cell therapies have proven effective in hematologic malignancies, patients with solid tumors have seen limited benefit from these approaches due to a tumor microenvironment that leads to T-cell exhaustion and a loss of durable stemness,” Tina Albertson, MD, PhD, chief medical officer and head of development, Lyell Immunopharma, said in a December 2021 statement regarding the IND clearance.² “LYL797 is the first program to clinically evaluate our 2 T-cell reprogramming technologies which are designed to overcome these barriers, with the goal of developing more effective therapies for patients with solid tumor cancers.”

The multi-center, single-arm, open-label, dose-escalation and dose-expansion trial will recruit up to 54 patients aged 18 years or older with locally advanced or metastatic, unresectable ROR1+ TNBC or NSCLC.¹ Participants are required to have measurable disease which includes a target lesion plus 1 additional lesion for biopsy, unless the target lesion is greater than or equal to 30 mm. Patients must additionally be r/r after having received 2 or more previous lines of therapy, have adequate organ and marrow function, and have an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 with a life expectancy greater than 3 months. Patients with active central nervous system disease or leptomeningeal disease, and patients who have undergone prior treatment with solid organ transplant, adoptive T-cell therapy, or anti-ROR1 therapy will be excluded from the study. However, patients with previously treated brain metastases, if stable, may be included. Additional exclusion criteria relate to patient health status, caregiver access, and locality to the treating facility.

The dose-escalation phase will enroll TNBC patients at 4 planned dose levels, with a 28-day dose-limiting toxicity (DLT) monitoring period, and will continue dose escalation until a recommended phase 2 dose (RP2D) is determined. The dose expansion phase will enroll 15 patients with TNBC and 15 patients with NSCLC at the RP2D. Patients will be pretreated with fludarabine and cyclophosphamide after leukapheresis and manufacturing, before receiving a single-dose infusion of LYL7978. Primary end points include the incidence of DLTs and the incidence and severity of treatment-emergent adverse events. Secondary end points include overall response rate, complete response rate, duration of response, progression-free survival, overall survival, and pharmacokinetic parameters. Exploratory end points include memory, activation, and exhaustion status of LYL797 CAR-T cells in the blood infusion product; ex vivo functional activity of LYL797 CAR-T cells before and after infusion; correlation between tumor-specific ROR1 expression and clinical activity; tumor infiltration; and tumor-specific expression of ROR1 and immune activation/resistance markers before and after treatment. The trial is recruiting at multiple locations in the United States and is estimated to be completed in September 2026.

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REFERENCES

1. Spigel DR, Murthy HS, Chumsri S, et al.Phase I study of LYL797, a ROR1-targeted CAR T-cell therapy with genetic and epigenetic reprogramming for the treatment of advanced solid tumors. Presented at: 2022 ESMO Congress. September 9-13, 2022; Paris, France. Abstract 777TiP

2. Lyell Immunopharma announces FDA clearance of its IND for LYL797, a CAR T-cell therapy incorporating novel reprogramming technologies for solid tumors. News release. Lyell Immunopharma, Inc. December 16, 2021. https://ir.lyell.com/news-releases/news-release-details/lyell-immunopharma-announces-fda-clearance-its-ind-lyl797-car-t