Virotherapy and checkpoint inhibitors can be combined for the treatment of cancer with complementarity and potential for synergistic effects. We have developed a cytolytic but non-replicative viral vector system based on Semliki Forest virus that encodes IL-12 (SFV-IL-12). Following direct intratumoral injection, infected cells release transgenic IL-12, die and elicit an inflammatory response triggered by both abundantly copied viral RNA and IL-12. In difficult to treat mouse cancer models, such as those derived from MC38 and bilateral B16-OVA, SFV-IL-12 synergized with an anti-PD-1 monoclonal antibody (mAb) to induce tumor regression and prolong survival. Similar synergistic effects were attained upon PD-L1 blockade. Combined SFV-IL-12 + anti-PD-1 mAb treatment only marginally increased the elicited CTL response over SFV-IL-12 as a single agent, at least when measured by in vivo killing assays. In contrast, we observed that SFV-IL-12 treatment induced expression of PD-L1 on tumor cells in an IFNγ-dependent fashion. PD-L1-mediated adaptive resistance thereby provides a mechanistic explanation of the observed synergistic effects achieved by the SFV-IL-12 + anti-PD-1 mAb combination.
- Received November 17, 2014.
- Revision received January 29, 2015.
- Accepted February 9, 2015.
- Copyright © 2015, American Association for Cancer Research.