Lyell Immunopharma, Inc. presented new nonclinical data at the 38th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) on innovations designed to shorten tumor infiltrating lymphocyte (TIL) manufacturing, LYL119, its second generation ROR1-targeted CAR T cell product candidate, as well as data on new technologies and the design of its two clinical trials in progress. New Nonclinical Data on LYL119, Innovation in Manufacturing and New Technologies: Four presentations highlight new nonclinical data from Lyell?s product pipeline and research programs, including: Lyell?s novel Epi-R? P2 manufacturing protocol to shorten delivery time of TIL product to patients; New nonclinical data on LYL119, Lyell?s second-generation ROR1-targeted CAR T-cell therapy; A new technology being advanced through a collaboration between Lyell and Outpace to enable tumor-restricted IL-12 activity to enhance solid tumor T cell therapies; and Lyell?s rejuvenation technology which has shown the potential to turn back the epigenetic clock to generate more stem-like T cells with reduced epigenetic age and enhanced proliferation ability. A presentation titled Epi-R P2 protocol produces a scalable polyclonal TIL product with a greater expansion success rate across hot and cold tumors in shorter culture time highlights Lyell?s Epi-R P2 manufacturing protocol that shortens manufacturing time for TIL while maintaining the desired yield, stemness phenotype and retention of tumor reactive clones.

Current TIL production time is approximately four to six weeks. Literature suggests that a shorter culture time is associated with improved cell quality, functionality and positive clinical outcomes in metastatic melanoma patients. Lyell?s Epi-R manufacturing protocols are designed to generate populations of TIL with stem-like properties to potentially improve antitumor activity.

Epi-R P2 is an improved TIL manufacturing process that reduces the TIL culture duration to less than three weeks without impacting the quality of TIL. New nonclinical data on LYL119, Lyell?s second-generation ROR1-targeted CAR T-cell therapy, is highlighted in a presentation titled Preclinical development of LYL119, a ROR1-targeted CAR T-cell product incorporating four novel T-cell reprogramming technologies to overcome barriers to effective cell therapy for solid tumors. LYL119 incorporates four of Lyell?s complementary, stackable T-cell reprogramming technologies to create potent ROR1-targeted CAR T cells with durable function.

In this study, LYL119 demonstrated superior cytotoxicity and sustained cytokine production upon repeated antigen stimulation compared to various controls lacking one or more of the reprogramming technologies and showed robust in vivo antitumor efficacy in a mouse xenograft tumor model at very low cell doses. A presentation titled Protein design and inducible expression allow context-dependent, localized IL-12 activity to enhance solid tumor T cell therapies highlights an innovative tumor-restricted IL-12 (trIL-12) technology that delivers potent IL-12 stimulation at the tumor site while avoiding systemic exposure. IL-12 is an immune-stimulatory cytokine that can induce potent anti-tumor activity, but systemic delivery of IL-12 has been shown to cause severe toxicity in patients.

trIL-12 was designed leveraging Outpace?s OutSmart? technology to rapidly auto-inactivate IL-12 after inducible secretion from engineered T cells with the aim of achieving safe, local delivery of IL-12 activity. trIL-12 is being advanced under a collaboration between Lyell and Outpace with the goal of improving efficacy for T-cell therapies while maintaining a favorable safety profile.

A presentation titled Rejuvenation of tumor-infiltrating lymphocytes (TIL) through Partial Reprogramming describes Lyell?s rejuvenation technology which has shown the potential to turn back the epigenetic clock to generate more stem-like T cells with reduced epigenetic age and enhanced proliferation ability. Previously published studies have demonstrated the decline in T-cell function as a person ages. These new nonclinical data show TIL rejuvenated with Lyell?s technology retain a broad TCR repertoire and demonstrate improved T-cell function and antitumor properties.

Clinical Trials in Progress: Two additional presentations highlight the design of Lyell?s two ongoing Phase 1 clinical trials in progress. A presentation titled Phase 1 trial of LYL797, a ROR1-targeted CAR T-cell therapy enhanced with genetic and epigenetic reprogramming, in advanced triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) describes the design of this dose-escalation, dose-expansion Phase 1 trial in patients with ROR1-positive relapsed refractory TNBC and NSCLC. A presentation titled Phase 1 trial of LYL845, an autologous tumor-infiltrating lymphocyte (TIL) therapy enhanced with epigenetic reprogramming, for the treatment of advanced solid tumors describes the design of this dose-escalation, dose-expansion Phase 1 trial in advanced solid tumors, including advanced melanoma, NSCLC and colorectal cancer.