Blood Journal
Leading the way in experimental and clinical research in hematology

ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells

  1. Sonia Guedan1,2,
  2. Xi Chen3,
  3. Aviv Madar3,
  4. Carmine Carpenito1,
  5. Shannon E. McGettigan1,
  6. Matthew J. Frigault1,
  7. Jihyun Lee1,
  8. Avery D. Posey Jr1,
  9. John Scholler1,
  10. Nathalie Scholler1,4,
  11. Richard Bonneau3,5, and
  12. Carl H. June1
  1. 1Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
  2. 2Translational Research Laboratory, Institut d’Investigació Biomèdica de Bellvitge–Institut Català d'Oncologia, Barcelona, Spain;
  3. 3Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY;
  4. 4Stanford Research Institute International, Biosciences Division, Menlo Park, CA; and
  5. 5Computer Science Department, Courant Institute of Mathematical Sciences, New York University, New York, NY

Key Points

  • ICOS-based CARs program bipolar TH17/TH1 cells with augmented effector function and in vivo persistence.

  • The expression of selected CAR endodomains can program T cells for their subsequent differentiation fates and effector functions.

Abstract

With the notable exception of B-cell malignancies, the efficacy of chimeric antigen receptor (CAR) T cells has been limited, and CAR T cells have not been shown to expand and persist in patients with nonlymphoid tumors. Here we demonstrate that redirection of primary human T cells with a CAR containing the inducible costimulator (ICOS) intracellular domain generates tumor-specific IL-17-producing effector cells that show enhanced persistence. Compared with CARs containing the CD3ζ chain alone, or in tandem with the CD28 or the 4-1BB intracellular domains, ICOS signaling increased IL-17A, IL-17F, and IL-22 following antigen recognition. In addition, T cells redirected with an ICOS-based CAR maintained a core molecular signature characteristic of TH17 cells and expressed higher levels of RORC, CD161, IL1R-1, and NCS1. Of note, ICOS signaling also induced the expression of IFN-γ and T-bet, consistent with a TH17/TH1 bipolarization. When transferred into mice with established tumors, TH17 cells that were redirected with ICOS-based CARs mediated efficient antitumor responses and showed enhanced persistence compared with CD28- or 4-1BB-based CAR T cells. Thus, redirection of TH17 cells with a CAR encoding the ICOS intracellular domain is a promising approach to augment the function and persistence of CAR T cells in hematologic malignancies.

  • Submitted October 27, 2013.
  • Accepted May 5, 2014.
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