Article Text
PDF
Abstract
Background Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) is a promising method for cancer treatment. Unlike other cell therapies that engineer the tumor-targeting receptor into the T cells, TIL therapy preserves and expands tumor-reactive T-cell clones from surgically resected tumors. TIL products that are highly enriched with tumor-reactive T-cell clones have been shown to mediate responses to treatment.1-3 Additionally, stem-like qualities of T cells have been associated with improved outcomes in patients treated with cellular therapies, including TIL.4 Therefore, a polyclonal TIL product containing diverse, potent tumor-targeting clones with stem-like qualities is vital for improving clinical outcomes in TIL therapy. LYL845 is an autologous TIL product produced with our proprietary Epi-RÔ epigenetic reprogramming protocol, which was developed to preserve polyclonality and tumor-reactive clones with enhanced stem-like qualities and anti-tumor function.
Methods LYL845 was generated using Epi-R technology and compared with TIL product generated by a standard protocol (as control). To identify tumor-reactive clones, we primarily rely on surrogate measures of clonal frequency and clonal phenotype,5-7 but also used tumor co-culture assays to directly measure tumor-reactivity. Using bulk TCR sequencing and CITE-seq + scTCR-seq, LYL845 was assessed for retainment of tumor-reactive clones.
Results We observed that both the research and large-scale TIL products expanded from multiple tumor types (melanoma, lung, colon) using Epi-R technology were highly polyclonal. Furthermore, putative tumor-reactive clones identified from initial tumor samples were preserved in LYL845, both at research (n=13) and large-scale (n=3). Using tumor co-culture assays, we confirmed that our approach for identifying putative-tumor reactive clones is a good surrogate for true tumor reactivity. The cells from putative tumor-reactive clones (and true tumor-reactive clones defined from co-culture assays) in LYL845 demonstrate more stem-like and effector function and less exhaustion than the putative tumor-reactive clones in the control products. In tumor co-culture assays, LYL845 demonstrates potent antitumor function, including dose-dependent cytolytic activities and cytokine secretion (figure 1).
Conclusions Pre-clinical data show that LYL845 is an expanded TIL product that preserves tumor-reactive clones with stem-like qualities. Based on these promising preclinical data, we plan to evaluate LYL845 for safety, tolerability, and anti-tumor activity in an upcoming first-in-human Phase 1 clinical trial.
Acknowledgements We thank members of Lyell Immunopharma’s flow cytometry core (Andrew Jimena, Elizabeth Pedrosa, Ken Xiong), process development team (Meritxell Galindo Casas, Carson Harms, Melissa DeFrancesco) and Queenie Vong for their experimental contributions.
References
van den Berg JH, Heemskerk B, van Rooij N, et al. Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up. J Immunother Cancer. 2020;8:e000848.
Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Clin Cancer Res. 2014;344:641-645.
Zacharakis N, Chinnasamy H, Black M, et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat Med. 2018;24:724-730.
Krishna S, Lowery FJ, Copeland AR. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science. 2020;370:1328-1334.
Oliviera G, Stromhaug K, Klaeger S, et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature. 2021;596:119-125.
Pasetto A, Gros A, Robbins PF, et al. Tumor- and neoantigen-reactive T-cell receptors can be identified based on their frequency in fresh tumor. Cancer Immunol Res. 2016;4:734-743.
Lowery FJ, Krishna S, Yossef R, et al. Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers. Science. 2022;875:977-884.
Ethics Approval Research was performed with tissues obtained from patients through a procurement protocol approved by WCG IRB, tracking number 20210857
Tumor recognition by the LYL845 product depicted as percent cytolysis with an autologous tumor cell line (metastatic melanoma). Tumor cell killing was observed in all E:T ratios compared to control- tumor only (0:1) in a dose-dependent manner.