Combination therapy with reovirus and Anti-PD-1 blockade controls tumor growth through innate and adaptive immune responses

Karishma Rajani, Christopher Parrish, Timothy Kottke, Jill Thompson, Shane Zaidi, Liz Ilett, Kevin G. Shim, Rosa Maria Diaz, Hardev Pandha, Kevin Harrington, Matt Coffey, Alan Melcher, Richard Vile

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Oncolytic reovirus can be delivered both systemically and intratumorally, in both preclinical models and in early phase clinical trials. Reovirus has direct oncolytic activity against a variety of tumor types and antitumor activity is directly associated with immune activation by virus replication in tumors. Immune mechanisms of therapy include both innate immune activation against virally infected tumor cells, and the generation of adaptive antitumor immune responses as a result of in vivo priming against tumor-associated antigens. We tested the combination of local oncolytic reovirus therapy with systemic immune checkpoint inhibition. We show that treatment of subcutaneous B16 melanomas with a combination of intravenous (i.v.) anti-PD-1 antibody and intratumoral (i.t.) reovirus significantly enhanced survival of mice compared to i.t. reovirus (P < 0.01) or anti-PD-1 therapy alone. In vitro immune analysis demonstrated that checkpoint inhibition improved the ability of NK cells to kill reovirus-infected tumor cells, reduced T reg activity, and increased the adaptive CD8 + T-cell-dependent antitumor T-cell response. PD-1 blockade also enhanced the antiviral immune response but through effector mechanisms which overlapped with but also differed from those affecting the antitumor response. Therefore, combination with checkpoint inhibition represents a readily translatable next step in the clinical development of reovirus viroimmunotherapy.

Original languageEnglish (US)
Pages (from-to)166-174
Number of pages9
JournalMolecular Therapy
Volume24
Issue number1
DOIs
StatePublished - Feb 1 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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