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

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.

PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy

“…+ T cells, the addition of anti-PD-1 therapy did not improve the efficacy of this therapeutic approach (50). Intratumorally administered reovirus in combination with systemic PD-1 blockade resulted in synergistic tumor growth inhibition, which was dependent on NK and CD8 + cells (47). Interestingly, in contrast to our findings with NDV, no significant PD-L1 induction was seen in that study in response to reovirus alone, and the induction of PD-L1 was attributed to the action of tumor-infiltrating NK cells (47).…”

“…Intratumorally administered reovirus in combination with systemic PD-1 blockade resulted in synergistic tumor growth inhibition, which was dependent on NK and CD8 + cells (47). Interestingly, in contrast to our findings with NDV, no significant PD-L1 induction was seen in that study in response to reovirus alone, and the induction of PD-L1 was attributed to the action of tumor-infiltrating NK cells (47). A study of combined oncolytic vaccinia and PD-L1 blockade demonstrated synergistic efficacy against the virus-treated peritoneal tumors, and the efficacy of such therapy was dependent on both CD4 + and CD8 + cells (44).…”

Metabolic regulation of immune responses: therapeutic opportunities

“…Together, these events facilitate glycolytic metabolism in tumor-infiltrating T cells and optimal antitumor functions. There is also evidence in patients with multiple myeloma that NK cells express PD-1 and that anti-PD-1 antibody treatment enhances NK cell antitumor function (33)(34)(35). It is tempting to speculate that the effect of anti-PD-1 antibodies on NK cell function is because these antibodies are preventing PD-1-mediated direct inhibition of NK cell glycolysis; however, another possibility is that the increased NK cell function is due to increased glucose availability jci.org Volume 126 Number 6 June 2016…”

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

“…In a B16 murine melanoma model, administration of systemic anti-PD-1 antibody along with intratumoral injection of reovirus significantly enhanced survival relative to reovirus alone (66). Immune analysis revealed that PD-1 antibody therapy enhanced the ability of NK cells to kill reovirus infected targets and that the combination therapy led to a reduction in Treg activity.…”