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BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia
Weimin Kong, … , Golnaz Vahedi, Joseph A. Fraietta
Weimin Kong, … , Golnaz Vahedi, Joseph A. Fraietta
Published August 16, 2021
Citation Information: J Clin Invest. 2021;131(16):1-16. https://doi.org/10.1172/JCI145459.
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Research Article Immunology Oncology Article has an altmetric score of 57

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

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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.

Authors

Weimin Kong, Alexander Dimitri, Wenliang Wang, In-Young Jung, Christopher J. Ott, Maria Fasolino, Yan Wang, Irina Kulikovskaya, Minnal Gupta, Todd Yoder, Jamie E. DeNizio, John K. Everett, Erik F. Williams, Jun Xu, John Scholler, Tyler J. Reich, Vijay G. Bhoj, Kathleen M. Haines, Marcela V. Maus, J. Joseph Melenhorst, Regina M. Young, Julie K. Jadlowsky, Katherine T. Marcucci, James E. Bradner, Bruce L. Levine, David L. Porter, Frederic D. Bushman, Rahul M. Kohli, Carl H. June, Megan M. Davis, Simon F. Lacey, Golnaz Vahedi, Joseph A. Fraietta

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Figure 4

JQ1 reinvigorates dysfunctional CAR T cells from nonresponding patients with CLL.

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JQ1 reinvigorates dysfunctional CAR T cells from nonresponding patients ...
(A) Spearman’s Rho correlation performed between the frequency of preinfusion CD8+PD-1+CAR+ T cells and the maximum proportion (Cmax) of in vivo expanded CD8+CAR+ T cells. Each dot represents an individual patient (n = 36) differentially colored according to therapeutic response. (B) CD8+CAR+ T cells were treated with 150–500 nM (–)-JQ1 or (+)-JQ1 for 4 days followed by evaluation of PD-1 levels. Flow cytometry histograms of PD-1 expression on CLL patient CAR+CD8+ T cells (left) are shown. PD-1 expression levels (middle) and proportions of CD8+CAR+ T cells after a 4-day incubation with 150 nM (–)-JQ1 or (+)-JQ1 are depicted (n = 11, paired t test). (C) CAR+ T cells were treated with (–)-JQ1 or (+)-JQ1 followed by stimulation with K562CD19 or K562CD19/PD-L1 cells. Functional properties of CAR T cells were then analyzed. (D) Proliferation of CAR T cells restimulated with K562 cells as indicated above (n = 3, paired t test). Arrows indicate stimulation time points. (E) Heatmap of cytokine profiles for CLL patient CAR T cells (n = 3) treated with (–)-JQ1 or (+)-JQ1 and stimulated with irradiated K562CD19 or K562CD19/PD-L1 cells is presented. Colors represent scaled cytokine data.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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