Many studies indicate that adoptive cell transfer therapy with autologous chimeric antigen receptor (CAR) T cells is a powerful approach for the treatment of cancer. CAR-modified T cells have shown activity in several clinical trials including our own at the University of Pennsylvania, with complete response rates as high as 80-90% in certain malignancies. However, the effectiveness of this approach for cancers involving T-cell defects, such as multiple myeloma, pancreatic cancer, and chronic lymphocytic leukemia (CLL), is much lower. The key questions currently facing the field are how to: i) enhance the potency and sustain the in vivo function of CAR T cells for such indications and ii) develop strategies to increase the resistance of CAR T cells to intrinsic and extrinsic dysfunction (e.g., immunosenescence, exhaustion, or other disease-specific defects). Because cell fate determination programs encoded in DNA are interpreted, modified, transmitted, and expanded as chromatin, we hypothesize that immunotherapy and reversal of T-cell dysfunction in cancer can be improved by broadly or specifically targeting appropriate epigenetic pathways. In this vein, we explore manipulation of the “writers” and “readers” of the histone code using genetic editing tools (e.g., CRISPR/Cas9) and chemical modifiers to convert poorly functional T cells to a state that renders these lymphocytes effective at tumor elimination. The basic understanding of T-cell biology in the context of epigenetic regulation may result in enhancement of cellular immunotherapy strategies, including the discovery of several actionable improvements to CAR T-cell therapy.

Citation Format: Joseph A. Fraietta. Reprogramming the epigenome for enhancing CAR T-cell antitumor efficacy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA13.