Abstract 1: Biomarkers of response and acquired resistance to TIL-ACT in solid tumors

Abstract Background: Cancer immunotherapy has revolutionized cancer treatment in the last decade. However, most patients either do not respond to immunotherapy or eventually relapse so there is a need to identify biomarkers of response and understand mechanisms of resistance. Most biomarker studies have analyzed patients treated with immune checkpoint inhibitors (CPI) therapy while the few studies of adoptive cell transfer of tumor infiltrating lymphocytes (TIL-ACT) have analyzed relatively small patient cohorts. Methods: To systematically identify biomarkers of response and resistance to TIL-ACT, we collected published and unpublished whole-exome and transcriptomic data for tumors from 400 patients treated with TIL-ACT from five tumor types across four institutions and processed these datasets using a standardized bioinformatic pipeline. Results: To identify biomarkers of response in pre-treatment tumors, we analyzed previously reported biomarkers and performed biomarker discovery in our cohorts. For the subset of 200 patients with T cell reactivities identified from the infusion products and fresh tumor, we refined our biomarkers to include neo-antigen reactivities in addition to identifying both mutational processes and transcriptional signatures associated with neo-antigens reactivity. To identify mechanisms of acquired resistance to TIL-ACT, we analyzed 15 patients with paired pre- and post-treatment tumors and found multiple mechanisms of immune evasion specific to infused reactive T cells including loss of heterozygosity of the HLA allele presenting the neo-antigen, genomic loss of the neo-antigen and inactivation of interferon-gamma signaling pathway. Conclusions: In summary, we will present the biomarkers landscape of TIL-ACT therapy including differences between histology and across treatment modalities to improve our understanding of the mechanisms of treatment response. Citation Format: Welles Robinson, Andrea Castro, Maise Al-Bakir, Jared J. Gartner, Christopher Aled Chamberlain, Anders H. Kverneland, Troels H. Borch, Inge Marie Svane, Marco Donia, Paul Robbins, Kevin Litchfield. Biomarkers of response and acquired resistance to TIL-ACT in solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1.