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Mol Ther. 2016 Feb;24(1):166-74. doi: 10.1038/mt.2015.156. Epub 2015 Aug 27.

Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses.

Author information

1
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
2
Cancer Research UK Clinical Centre, St. James' University Hospital, Leeds, UK.
3
University of Surrey, Guildford, UK.
4
The Institute of Cancer Research, London, UK.
5
Oncolytics Biotech Incorporated, Calgary, Alberta, Canada.
6
Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.

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.

PMID:
26310630
PMCID:
PMC4754544
DOI:
10.1038/mt.2015.156
[Indexed for MEDLINE]
Free PMC Article

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