On November 7, 2022 Lyell Immunopharma, Inc. (Nasdaq: LYEL), a clinical-stage T-cell reprogramming company dedicated to developing curative cell therapies for patients with solid tumors, is presenting preclinical data at the 37th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) on its product candidates and new genetic and epigenetic reprogramming technologies (Press release, Lyell Immunopharma, NOV 7, 2022, View Source [SID1234623252]). This includes new preclinical research on the potential to generate more potent T cells to provide durable anti-tumor functions against certain aggressive solid tumor cancers.
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"Our SITC (Free SITC Whitepaper) presentations showcase compelling preclinical data underlying our lead TIL product candidate, LYL845, as well as the exciting progress Lyell’s research team is making to advance our understanding of how to counter T-cell exhaustion and generate T cells with properties of durable stemness," said Gary Lee, Ph.D., chief scientific officer at Lyell. "We are applying this research to grow our pipeline by creating new stackable reprogramming technologies as we continue to work toward our mission of developing adoptive T-cell therapies that deliver consistent, reliable and durable responses in solid tumors."
Preclinical Data on LYL845
Two presentations on Friday, Nov. 11 highlight preclinical data on LYL845, Lyell’s tumor-infiltrating lymphocyte (TIL) product candidate being evaluated for safety, tolerability and anti-tumor activity in a first-in-human Phase 1 clinical trial (NCT05573035). (Abstract Nos. 370 and 340).
The first presentation, titled "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," showcases the ability of Epi-R technology to successfully expand TIL across three tumor types as compared to the standard (control) process. In this study, expanding TIL with Epi-R technology resulted in 100 percent success rate vs. 70 percent with control, including tumor samples collected from checkpoint inhibitor experienced melanoma patients. The study also includes colorectal tumor samples which have been considered more challenging to expand with standard processes. Further, in this study Epi-R technology yielded a product (LYL845) with a greater proportion of CD8+ T-cells and enriched for T-cells with stem-like profiles, better metabolic fitness, and preserved polyclonality compared to control TIL. These qualities have been linked with anti-tumor functionality and improved outcomes in previous TIL clinical trials.
The second presentation, titled "The Epi-R technology produces a polyclonal TIL product (LYL845) with diverse tumor-reactive clones that have stem-like qualities and anti-tumor function," highlights bioinformatic analyses demonstrating that LYL845 products expanded using Epi-R technology were highly polyclonal and retained putative tumor reactive clones with increased stemness and reduced exhaustion-associated genes compared to TIL products derived from the standard process. Moreover, tumor-specific reactivities of LYL845 were confirmed, and anti-tumor functions, including dose-dependent cytolytic activities and cytokine secretion, in tumor cell specific co-culture assays were demonstrated.
Stackable Genetic and Epigenetic Reprogramming Technologies in LYL119, a Second-Generation CAR T-cell therapy targeting ROR1+ solid tumors
Two presentations describe preclinical data on Lyell’s new, stackable reprogramming technologies – NR4A3 knockout and Stim-R – being incorporated in LYL119, a second-generation ROR1 targeting CAR T-cell product candidate.
An abstract titled "NR4A3 gene editing and c-Jun overexpression synergize to limit exhaustion and enhance functional activity of ROR1 CAR T cells in vitro and in vivo" being presented on Thursday, Nov. 10 demonstrates that the combination of two genetic reprogramming technologies, NR4A3 gene knockout and c-Jun overexpression, enhances the functional activity of ROR1 CAR T cells. This is demonstrated by higher levels of cytokine production, increased CAR T-cell persistence and reduced surface expression of inhibitory receptors after repetitive antigen stimulation, as well as significant improvement in tumor control in vivo (Abstract No. 243). NR4A3 and c-Jun both function within the activator protein 1 (AP-1) transcription factor pathway, which plays a key role in regulating T-cell function. This new research furthers the hypothesis that reprogramming of AP-1 transcription factor pathway in T cells may delay exhaustion and improve anti-tumor function. Lyell plans to incorporate these two stackable genetic reprogramming technologies in its new product candidate, LYL119, currently in preclinical development.
An abstract titled "Engineering potent CAR T-cell therapies by controlling T-cell activation signaling parameters using the Stim-R technology, a programmable synthetic cell-signaling platform" being presented on Friday, Nov. 11 describes Stim-R, Lyell’s new epigenetic reprogramming technology. Stim-R is a synthetic cell mimic that mediates precise signal molecule presentation to generate arrays of diverse ROR1-targeted CAR T-cell products (Abstract No. 252). This research demonstrates that Stim-R generates potent CAR T-cell products with increased polyfunctionality, persistence, anti-tumor activity, and reduced exhaustion following repeated antigen stimulation in vitro. These cells also showed greater CAR T-cell proliferation and persistence in vivo, as well as improved tumor control. Lyell also plans to incorporate this technology in LYL119.