Localized Oncolytic Virotherapy Has Distant Antitumor Effects

Localized administration of oncolytic viruses that preferentially infect and kill cancer cells has shown antitumor activity, but the effects on distant or metastatic tumors are unknown. To recapitulate the effects of localized oncolytic virotherapy on metastatic disease, Zamarin and colleagues used a bilateral flank tumor model in which only one tumor was injected with Newcastle disease virus (NDV), a nonpathogenic oncolytic virus that has been safely used in clinical trials. Although viral replication was limited to the injection site, NDV treatment stimulated a potent inflammatory response that delayed growth and induced infiltration by innate and effector T cells of both local and distant tumors. This NDV-driven response was tumor antigen specific and required CD8⁺ T cells, natural killer cells, and type I IFN. However, NDV therapy only induced complete contralateral tumor regression in approximately 10% of treated mice, suggesting that immunosuppressive tumor microenvironments limited the effect of the NDV-induced inflammatory response. Consistent with this possibility, the T-cell inhibitory receptor cytotoxic T-lymphocyte antigen 4 (CTLA-4) was upregulated on tumor-infiltrating T cells, prompting the authors to hypothesize that NDV therapy might sensitize tumors to CTLA-4 blockade. Indeed, combining localized NDV therapy with systemic anti-CTLA-4 antibody therapy led to greater bilateral tumor rejection, long-term survival, and protection against tumor rechallenge than either agent alone. The efficacy of this combination therapy was successfully extended to cancer cell types that are known to be strongly resistant to virus-mediated lysis, further demonstrating that NDV mediates its antitumor effects by stimulating the innate and adaptive immune system rather than by direct lysis. In addition to showing that localized oncolytic therapy activates a tumor-specific systemic antitumor inflammatory response that enhances lymphocyte infiltration of distant tumors, these findings provide a rationale for combination immunotherapy with oncolytic viruses and immune checkpoint inhibitors.

Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med 2014;6:226ra32.

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