Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity

Mol Ther. 2016 Aug;24(8):1444-55. doi: 10.1038/mt.2016.121. Epub 2016 Jun 10.

Abstract

Cytomegalovirus is an attractive cancer vaccine platform because it induces strong, functional CD8(+) T-cell responses that accumulate over time and migrate into most tissues. To explore this, we used murine cytomegalovirus expressing a modified gp100 melanoma antigen. Therapeutic vaccination by the intraperitoneal and intradermal routes induced tumor infiltrating gp100-specific CD8(+) T-cells, but provided minimal benefit for subcutaneous lesions. In contrast, intratumoral infection of established tumor nodules greatly inhibited tumor growth and improved overall survival in a CD8(+) T-cell-dependent manner, even in mice previously infected with murine cytomegalovirus. Although murine cytomegalovirus could infect and kill B16F0s in vitro, infection was restricted to tumor-associated macrophages in vivo. Surprisingly, the presence of a tumor antigen in the virus only slightly increased the efficacy of intratumoral infection and tumor-specific CD8(+) T-cells in the tumor remained dysfunctional. Importantly, combining intratumoral murine cytomegalovirus infection with anti-PD-L1 therapy was synergistic, resulting in tumor clearance from over half of the mice and subsequent protection against tumor challenge. Thus, while a murine cytomegalovirus-based vaccine was poorly effective against established subcutaneous tumors, direct infection of tumor nodules unexpectedly delayed tumor growth and synergized with immune checkpoint blockade to promote tumor clearance and long-term protection.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • B7-H1 Antigen / antagonists & inhibitors*
  • Cancer Vaccines / genetics
  • Cancer Vaccines / immunology
  • Combined Modality Therapy
  • Gene Expression
  • Gene Order
  • Genes, Reporter
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Immunity*
  • Immunotherapy
  • Macrophages / immunology
  • Macrophages / metabolism
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / metabolism*
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / therapy
  • Mice
  • Muromegalovirus / physiology*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Treatment Outcome
  • Tumor Burden
  • Vaccination
  • gp100 Melanoma Antigen / genetics

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • B7-H1 Antigen
  • Cancer Vaccines
  • gp100 Melanoma Antigen