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

  • 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.

  • 1Department of Microbiology,

    2Center for Cellular Immunotherapies,

    3Abramson Cancer Center, and

    4Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    5Department of Medicine, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, USA.

    6Department of Medicine and

    7Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    8Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    9Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    10Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.

    11Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Joseph A. Fraietta, Department of Microbiology, Perelman School of Medicine, South Pavilion Expansion (SPE), Room 9-104, 3400 Civic Center Boulevard, Building 421, Philadelphia, Pennsylvania 19104-5156, USA. Phone: 215.746.4083; Email: [email protected].

Received October 26, 2020

Accepted July 6, 2021

Journal of Clinical Investigation 131(16):p e145459, August 16, 2021. | 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.

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