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- Title
BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia.
- Authors
Weimin Kong; Dimitri, Alexander; Wenliang Wang; In-Young Jung; Ott, Christopher J.; Fasolino, Maria; Wang, Yan; Kulikovskaya, Irina; Gupta, Minnal; Yoder, Todd; DeNizio, Jamie E.; Everett, John K.; Williams, Erik F.; Jun Xu; Scholler, John; Reich, Tyler J.; Bhoj, Vijay G.; Haines, Kathleen M.; Maus, Marcela V.; Melenhorst, J. Joseph
- 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.
- Subjects
CHRONIC lymphocytic leukemia; T cells; CHIMERIC antigen receptors; T cell receptors; B cell lymphoma; FLUDARABINE; PHENOTYPIC plasticity; CHRONIC lymphocytic leukemia treatment; BROMODOMAIN-containing proteins; PROTEINS; AZEPINES; IMMUNOLOGICAL tolerance; ENERGY metabolism; RESEARCH; IMMUNIZATION; HETEROCYCLIC compounds; RESEARCH methodology; EVALUATION research; COMPARATIVE studies; GENES; IMMUNITY; RESEARCH funding; GLYCOLYSIS; ANTIGENS; CHEMICAL inhibitors
- Publication
Journal of Clinical Investigation, 2021, Vol 131, Issue 16, p1
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI145459