Modulation of intracellular kinase signaling to improve TIL manufacturing for adoptive cell therapy.

Abstract Tumor-infiltrating lymphocytes (TILs) has demonstrated significant clinical benefits for patients with solid tumor. A robust expansion process is needed in order to produce a large number of cells for clinical usage. We modulated the PI3K-AKT signaling pathway in TILs isolated from cervical and ovarian cancer patients and found the inhibition of either PI3K or AKT can promote TIL proliferation during the REP stage. Inhibiting PI3K-AKT led to an increase of the effector CD8+T cell population with higher CD25+ and CD28+ in the CD8+ population, more TCF-1+ and CD39-CD69- T cells in both CD4+ and CD8+ T cell population, and downregulated exhaustion markers CD39+ and TIM-3+ in CD8+ T cell population. This inhibition significantly increased cytotoxicity when cocultured with tumor cell lines and patient-derived tumor samples. Moreover, dual knockout of ATK1 and ATK2 promoted TIL proliferation, long-term survival and decreased apoptosis of TIL, which were further confirmed by the RNA-seq results. Thus, inhibition of PI3K-AKT signaling represents a promising strategy to generate large numbers of TIL with enhanced stemness, activation and cytotoxicity, and could be used to support adoptive cell therapy to treat solid tumors. Citation Format: Zixiao Shi, Sheng Yao, Peipei Zhao, Fei Li, Di Zhou, Jun Cui, Jingwei Sun, Yarong Liu. Modulation of intracellular kinase signaling to improve TIL manufacturing for adoptive cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5582.