ICOS Costimulation at the Tumor Site in Combination with CTLA-4 Blockade Therapy Elicits Strong Tumor Immunity

Mol Ther. 2019 Nov 6;27(11):1878-1891. doi: 10.1016/j.ymthe.2019.07.013. Epub 2019 Jul 25.

Abstract

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy is able to induce long-lasting antitumor responses in a fraction of cancer patients. Nonetheless, there is still room for improvement in the quest for new therapeutic combinations. ICOS costimulation has been underscored as a possible target to include with CTLA-4 blocking treatment. Herein, we describe an ICOS agonistic aptamer that potentiates T cell activation and induces stronger antitumor responses when locally injected at the tumor site in combination with anti-CTLA-4 antibody in different tumor models. Furthermore, ICOS agonistic aptamer was engineered as a bi-specific tumor-targeting aptamer to reach any disseminated tumor lesions after systemic injection. Treatment with the bi-specific aptamer in combination with CTLA-4 blockade showed strong antitumor immunity, even in a melanoma tumor model where CTLA-4 treatment alone did not display any significant therapeutic benefit. Thus, this work provides strong support for the development of combinatorial therapies involving anti-CTLA-4 blockade and ICOS agonist tumor-targeting agents.

Keywords: CTLA-4; ICOS; aptamer; cancer immunotherapy; target therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / pharmacology
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Agents, Immunological / therapeutic use
  • CTLA-4 Antigen / antagonists & inhibitors*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Immunomodulation / drug effects*
  • Inducible T-Cell Co-Stimulator Protein / agonists
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Melanoma, Experimental
  • Mice
  • Models, Biological
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Tumor Burden

Substances

  • Antibodies, Bispecific
  • Antineoplastic Agents, Immunological
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Icos protein, mouse
  • Inducible T-Cell Co-Stimulator Protein