title: ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells.
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.
authors.affiliation: 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;
authors.forename: Sonia
authors.initials: S
authors.lastname: Guedan
authors.affiliation: Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY;
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY;
authors.forename: Aviv
authors.initials: A
authors.lastname: Madar
authors.affiliation: Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Carmine
authors.initials: C
authors.lastname: Carpenito
authors.affiliation: Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Shannon E
authors.initials: SE
authors.lastname: McGettigan
authors.affiliation: Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Frigault
authors.affiliation: Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Jihyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Avery D
authors.initials: AD
authors.lastname: Posey
authors.affiliation: Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: John
authors.initials: J
authors.lastname: Scholler
authors.affiliation: 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.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Scholler
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
authors.affiliation: Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology* / Q000378:metabolism; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D020014:K562 Cells; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097043:Interleukin-22
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D060889:Inducible T-Cell Co-Stimulator Protein; D053631:Interleukin Receptor Common gamma Subunit; D020381:Interleukin-17; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000097043:Interleukin-22; C121704:CD3 antigen, zeta chain; C507942:Il2rg protein, mouse