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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • 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

Substances

  • CD28 Antigens
  • CD3 Complex
  • CD3 antigen, zeta chain
  • Il2rg protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-17
  • Interleukins
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor Receptor Superfamily, Member 9