BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia

• Published in: The Journal of clinical investigation Vol. 131; no. 16; pp. 1 - 16
• Main Authors: Kong, Weimin, Dimitri, Alexander, Wang, Wenliang, Jung, In-Young, Ott, Christopher J, Fasolino, Maria, Wang, Yan, Kulikovskaya, Irina, Gupta, Minnal, Yoder, Todd, DeNizio, Jamie E, Everett, John K, Williams, Erik F, Xu, Jun, Scholler, John, Reich, Tyler J, Bhoj, Vijay G, Haines, Kathleen M, Maus, Marcela V, Melenhorst, J. Joseph, Young, Regina M, Jadlowsky, Julie K, Marcucci, Katherine T, Bradner, James E, Levine, Bruce L, Porter, David L, Bushman, Frederic D, Kohli, Rahul M, June, Carl H, Davis, Megan M, Lacey, Simon F, Vahedi, Golnaz, Fraietta, Joseph A
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 15.08.2021
• Subjects: Antigen receptors, T cell; Antigens; Antitumor activity; Bet protein; Biomedical research; Care and treatment; CD19 antigen; Cellular therapy; Chimeric antigen receptors; Chromatin; Chronic lymphocytic leukemia; Dioxygenase; Effector cells; Epigenetics; Extinction; Gene expression; Genetic aspects; Health aspects; Immunotherapy; Leukemia; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Methods; Patients; Pharmacodynamics; Polypeptides; Proteins; Receptors; Remission (Medicine); T cell receptors; T cells; United States
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI145459

Chimeric antigen receptor (CAR) T cells have induced remarkable antitumor responses in B cell malignancies. Some patients do not respond because of T cell deficiencies that hamper the expansion, persistence, and effector function of these cells. We used longitudinal immune profiling to identify phenotypic and pharmacodynamic changes in CD19-directed CAR T cells in patients with chronic lymphocytic leukemia (CLL). CAR expression maintenance was also investigated because this can affect response durability. CAR T cell failure was accompanied by preexisting T cell-intrinsic defects or dysfunction acquired after infusion. In a small subset of patients, CAR silencing was observed coincident with leukemia relapse. Using a small molecule inhibitor, we demonstrated that the bromodomain and extra-terminal (BET) family of chromatin adapters plays a role in downregulating CAR expression. BET protein blockade also ameliorated CAR T cell exhaustion as manifested by inhibitory receptor reduction, enhanced metabolic fitness, increased proliferative capacity, and enriched transcriptomic signatures of T cell reinvigoration. BET inhibition decreased levels of the TET2 methylcytosine dioxygenase, and forced expression of the TET2 catalytic domain eliminated the potency-enhancing effects of BET protein targeting in CAR T cells, providing a mechanism linking BET proteins and T cell dysfunction. Thus, modulating BET epigenetic readers may improve the efficacy of cell-based immunotherapies.