Abstract LB067: Tumor-reactive CD8 TIL with an exhausted phenotype can be expanded and regress human tumors

Abstract Tumor-reactive human CD8 T cells are found predominantly in the tumor microenvironment with an exhausted phenotype (extremely high levels of CD39, PD-1, CTLA-4, and TIM-3). The tumor-reactive cells can be enriched from patients’ tumors by sorting CD8+ TIL that express both CD39 and CD103. Our unique expansion method allowed these phenotypically exhausted cells to grow from thousands into billions. After expansion the CD39 and CD103 Double Positive (DP) CD8 TIL can recognize/kill autologous tumor cells in vitro. We tested whether the CD8 DP TIL could recognize/kill autologous tumor in vivo using a xenograft model with immune-compromised mice that constitutively secrete human IL-2 (NOG-hIL-2). The CD8 DP TIL were able to persist long-term, traffic to the tumor site, recognize autologous tumor, and facilitate tumor regression. Human IL-2 was necessary for their long-term survival in the periphery and for tumor regression. These preclinical data were the basis for a human clinical trial design for the adoptive transfer of CD8 DP TIL (product termed, AGX148). We recently opened a Phase 1 clinical trial using the CD39/103 DP CD8 TIL in a first-in-human protocol for adults with solid tumors (NCT05902520). The trial design has three cohorts based on giving IL-2 for 2 weeks, 3 weeks, or 4 weeks after adoptive transfer with six patients/cohort (3 receiving DP TIL alone and 3 receiving DP TIL combined with PD-1 siRNA knockdown with the INTASYLTM compound PH-762). The first 3 patients have been treated and received 27, 40, and 8 billion DP TIL, respectively. All 3 patients had failed standard therapy prior to their enrollment, including checkpoint blockade. No serious adverse events were observed in the first three patients. Two of three patients had partial responses 29 days after treatment and the third patient had stable disease for >56 days. Blood draws and tumor biopsies were obtained prior to and after treatment and we are currently assessing the CD8 T cell repertoire (TCRseq) and phenotype from these patient samples. In conclusion, this is the first study showing that CD8 T cells with an exhausted phenotype isolated from human tumors can be expanded to billions and induce tumor regression in vivo. Citation Format: Andrew Weinberg, Brendan Curti, Ryan Montler, Colin Thalhofer, Elaine Ballinger, Jessica Cross, Eric Tran, Nelson Sanjuan, Matthew Taylor, Christopher Fountain, Roxanne Payne, James Cardia, Nicholas Morris. Tumor-reactive CD8 TIL with an exhausted phenotype can be expanded and regress human tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB067.