Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy

J Exp Med. 2014 Apr 7;211(4):715-25. doi: 10.1084/jem.20130590. Epub 2014 Mar 31.

Abstract

Cytotoxic T lymphocyte antigen-4 (CTLA-4) blockade with a monoclonal antibody yields durable responses in a subset of cancer patients and has been approved by the FDA as a standard therapy for late-stage melanoma. We recently identified inducible co-stimulator (ICOS) as a crucial player in the antitumor effects of CTLA-4 blockade. We now show that concomitant CTLA-4 blockade and ICOS engagement by tumor cell vaccines engineered to express ICOS ligand enhanced antitumor immune responses in both quantity and quality and significantly improved rejection of established melanoma and prostate cancer in mice. This study provides strong support for the development of combinatorial therapies incorporating anti-CTLA-4 and ICOS engagement.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antigen Presentation / drug effects
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CTLA-4 Antigen / antagonists & inhibitors*
  • CTLA-4 Antigen / metabolism
  • Cancer Vaccines / immunology
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Immunologic Memory / drug effects
  • Immunosuppression
  • Immunotherapy*
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Ligands
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Mice
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / prevention & control
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Up-Regulation / drug effects

Substances

  • Antibodies, Monoclonal
  • CTLA-4 Antigen
  • Cancer Vaccines
  • Cytokines
  • Icos protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • Ligands