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Blood. 2014 Aug 14;124(7):1070-80. doi: 10.1182/blood-2013-10-535245. Epub 2014 Jul 1.

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

Author information

1
Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Translational Research Laboratory, Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia, Barcelona, Spain;
2
Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY;
3
Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
4
Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Stanford Research Institute International, Biosciences Division, Menlo Park, CA; and.
5
Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY; Computer Science Department, Courant Institute of Mathematical Sciences, New York University, New York, NY.

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.

PMID:
24986688
PMCID:
PMC4133482
DOI:
10.1182/blood-2013-10-535245
[Indexed for MEDLINE]
Free PMC Article

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