Abstract 2815: Exploring the role of telomerase in senescence and exhaustion in CAR T cell immunotherapy

Abstract Chimeric antigen receptor (CAR) T cell therapy has revolutionized oncology through engineered targeting of antigens on previously untreatable cancers. However, less than half of patients on CAR T cell therapy experience long-term disease control, with better outcomes observed in pediatric compared to adult populations. Senescent T cells have been shown to manifest defective killing abilities and the development of negative regulatory functions, with evidence suggesting that senescence may play a role in decreasing CAR T cell efficacy and persistence. Moreover, levels of telomerase have been shown to control the lifespan of human T cells, with increased levels delaying senescence. It has been shown that T cell exhaustion limits CAR T cell efficacy in the context of solid tumors, where CAR T cells have yet to demonstrate sustained responses. Using a model of CAR T cell exhaustion developed in our lab, and CAR T cells manufactured from younger and older donors, we have developed a comprehensive method to profile T cell functionality, phenotype, and proliferation. We are able to characterize features of senescence via cell surface markers, intracellular activity, telomere length, and telomerase activity as well as features of exhaustion. Using CRISPR/Cas9, we have inactivated TERT in primary human T cells and CAR T cells and interrogated the effects of hTERT knockout as well as of hTERT overexpression on key markers of T cell identity, exhaustion, senescence, and cytotoxic activity. Understanding telomerase in the context of CAR T cell therapy will provide mechanistic insights into senescence and exhaustion cellular programs and has the potential to inform increasingly effective CAR T cell cancer treatments. Citation Format: Tara Murty, Maria C. Ramello, Elena Sotillo, Lu Chen, Steven A. Artandi, Crystal L. Mackall. Exploring the role of telomerase in senescence and exhaustion in CAR T cell immunotherapy [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 2815.