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

Sonia Guedan, Xi Chen, Aviv Madar, Carmine Carpenito, Shannon E. McGettigan, Matthew J. Frigault, Jihyun Lee, Avery D. Posey, John Scholler, Nathalie Scholler, Richard Bonneau, Carl H. June

Research output: Contribution to journalArticle

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 T H17 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 CARsmediated efficient antitumor responses and showedenhanced 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.

Original languageEnglish (US)
Pages (from-to)1070-1080
Number of pages11
JournalBlood
Volume124
Issue number7
DOIs
StatePublished - Aug 14 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Guedan, S., Chen, X., Madar, A., Carpenito, C., McGettigan, S. E., Frigault, M. J., Lee, J., Posey, A. D., Scholler, J., Scholler, N., Bonneau, R., & June, C. H. (2014). ICOS-based chimeric antigen receptors program bipolar TH17/ TH1 cells. Blood, 124(7), 1070-1080. https://doi.org/10.1182/blood-2013-10-535245