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

• Published in: Blood Vol. 124; no. 7; pp. 1070 - 1080
• Main Authors: Guedan, Sonia, Chen, Xi, Madar, Aviv, Carpenito, Carmine, McGettigan, Shannon E., Frigault, Matthew J., Lee, Jihyun, Posey, Avery D., Scholler, John, Scholler, Nathalie, Bonneau, Richard, June, Carl H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.08.2014; American Society of Hematology
• Subjects: Animals; CD28 Antigens - genetics; CD28 Antigens - immunology; CD28 Antigens - metabolism; CD3 Complex - genetics; CD3 Complex - immunology; CD3 Complex - metabolism; Cell Line, Tumor; Cells, Cultured; Flow Cytometry; Gene Therapy; Humans; Immunotherapy, Adoptive - methods; Inducible T-Cell Co-Stimulator Protein - immunology; Inducible T-Cell Co-Stimulator Protein - metabolism; Interleukin Receptor Common gamma Subunit - genetics; Interleukin-17 - immunology; Interleukin-17 - metabolism; Interleukin-22; Interleukins - immunology; Interleukins - metabolism; K562 Cells; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - metabolism; Signal Transduction - genetics; Signal Transduction - immunology; Th1 Cells - immunology; Th1 Cells - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism; Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-10-535245

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. •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.