1. BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia.
- Author
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Kong W, Dimitri A, Wang W, Jung IY, Ott CJ, Fasolino M, Wang Y, Kulikovskaya I, Gupta M, Yoder T, DeNizio JE, Everett JK, Williams EF, Xu J, Scholler J, Reich TJ, Bhoj VG, Haines KM, Maus MV, Melenhorst JJ, Young RM, Jadlowsky JK, Marcucci KT, Bradner JE, Levine BL, Porter DL, Bushman FD, Kohli RM, June CH, Davis MM, Lacey SF, Vahedi G, and Fraietta JA
- Subjects
- Antigens, CD19 immunology, Azepines pharmacology, Epigenesis, Genetic, Glycolysis drug effects, Humans, Immune Tolerance, Immunologic Memory, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Oxidative Phosphorylation drug effects, Receptors, Chimeric Antigen genetics, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Triazoles pharmacology, Immunotherapy, Adoptive, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Proteins antagonists & inhibitors, Proteins immunology, Receptors, Chimeric Antigen immunology, T-Lymphocytes immunology
- Abstract
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.
- Published
- 2021
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