Background Chimeric antigen receptor (CAR) T-cell therapy has been successful for the treatment of lymphoid malignancies but remains challenging for solid tumors due to biological obstacles such as T-cell exhaustion and lack of durable stemness.¹ LYL797 is an investigational, autologous ROR1-targeted CAR T-cell product enhanced with genetic and epigenetic reprogramming technologies designed to generate products that overcome these barriers to optimize efficacy in solid tumors. Through c-Jun overexpression and Epi-R™ manufacturing protocols, Lyell’s reprogramming technologies generate T-cell populations with improved proliferation, reduced exhaustion, and stem-like characteristics that result in durable anti-tumor activity in preclinical studies.^1–5 ROR1 was selected as a target due to its high expression in several solid tumor types, including TNBC (~60%) and NSCLC (~40%).⁶

Methods LYL797–101 is a Phase 1, first-in-human, multicenter, single-arm, open label, dose-escalation and -expansion trial (NCT05274451) to evaluate the safety and anti-tumor activity of LYL797 in adult patients (pts) with locally advanced or metastatic, unresectable ROR1+ (determined at a central laboratory by an investigational clinical trial assay) TNBC or NSCLC. Pts must have received at least one (NSCLC) or two (TNBC) prior lines of systemic therapy appropriate for their disease. Other key eligibility requirements include ECOG status 0–1 and adequate organ function. Pts with treated, stable, and asymptomatic brain metastases are eligible for the study.

The study will treat up to 54 adult pts with TNBC or NSCLC in the dose-escalation and -expansion phases. The dose-escalation phase contains 4 planned dose levels and uses a novel Bayesian interval design, the modified toxicity probability interval 2 (mTPI2), for dose finding, with a 28-day dose-limiting toxicity (DLT) period. Dose escalation will continue until a recommended phase 2 dose (RP2D) is selected for evaluation in the dose-expansion phase.

LYL797 is manufactured for each pt from cells obtained via leukapheresis. Bridging therapy (chemotherapy and/or radiation) is allowed after leukapheresis. After successful LYL797 manufacturing, pts receive fludarabine and cyclophosphamide followed by a single infusion of LYL797 at the protocol-assigned dose level. Study objectives include assessment of safety and tolerability (primary), as well as anti-tumor activity and pharmacokinetics (secondary) of LYL797. Additional exploratory objectives include evaluation of the effects of Lyell’s genetic and epigenetic reprogramming technologies on T-cell phenotype and activity, as well as evaluation of the relationship between ROR1 expression and LYL797 activity. The trial is currently open

Trial Registration NCT05274451

References

1. Park S, Simianer C, Spadinger S, et al. LYL797, a ROR1 CAR T-cell therapy with genetic and epigenetic reprogramming for solid tumors. Cancer Res. 2022;82(12_Suppl):2754–2754.

2. Lynn RC, Weber EW, Sotillo E, et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature. 2019;576:293–300.

3. Patel Y, Harris B, Bedard M, et al. The Epi-R technology produces a polyclonal TIL product (LYL845) with a greater expansion success rate across hot and cold tumors, improved product phenotype, and maintenance of TCR diversity. J ImmunoTher Cancer. 2022;10(Suppl 2):A389.

4. Harris BD, Patel Y, Ha N-H, et al. Epi-R technology produces a polyclonal TIL product (LYL845) with diverse tumor-reactive clones that have stem-like qualities and anti-tumor function. J ImmunoTher Cancer. 2022;10(Suppl 2):A358.

5. Park S, Wang X, Simianer C, et al. Preclinical development of LYL797, a ROR1-targeted CAR T-cell therapy enhanced with genetic and epigenetic reprogramming for solid tumors. Mol Ther. 2022;30:311–311.

6. Balakrishnan A, Goodpaster T, Randolph-Habecker J, et al. Analysis of ROR1 protein expression in human cancer and normal tissues. Clin Cancer Res. 2017;23:3061–3071.

Ethics Approval This trial was approved by a central IRB (Advarra; MOD01229690) and individual clinical sites’ IRBs. All patients gave written informed consent before participating in the trial.