Cancer Immunology Miniatures Virotherapy with a Semliki Forest Virus–Based Vector Encoding IL12 Synergizes with PD-1/PD-L1 Blockade

Virotherapy and checkpoint inhibitors can be combined for the treatment of cancer with complementarity and potential for syn-ergistic effects. We have developed a cytolytic but nonreplicative viral vector system based on Semliki Forest virus that encodes IL12 (SFV-IL12). Following direct intratumoral injection, infected cells release transgenic IL12, die, and elicit an inflammatory response triggered by both abundantly copied viral RNA and IL12. In difficult-to-treat mouse cancer models, such as those derived from MC38 and bilateral B16-OVA, SFV-IL12 synergized with an anti– PD-1monoclonal antibody (mAb) to induce tumor regression and prolong survival. Similar synergistic effects were attained upon PD-L1 blockade. Combined SFV-IL12þ anti–PD-1mAb treatment only marginally increased the elicited cytotoxic T-lymphocyte response over SFV-IL12 as a single agent, at least when measured by in vivo killing assays. In contrast, we observed that SFV-IL12 treatment induced expression of PD-L1 on tumor cells in an IFNg-dependent fashion. PD-L1–mediated adaptive resistance thereby provides a mechanistic explanation of the observed synergistic effects achieved by the SFV-IL12 þ anti–PD-1 mAb combination. Cancer Immunol Res; 3(5); 449–54. 2015 AACR