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

Abstract

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 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-1 monoclonal antibody (mAb) to induce tumor regression and prolong survival. Similar synergistic effects were attained upon PD-L1 blockade. Combined SFV-IL12 þ anti-PD-1 mAb 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 IFNgdependent 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.

Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming

“…1A), known to be of difficult treatment by immunotherapy (32,33). In this case, mice bearing tumors for 11 days showed a radiotherapy-dependent control of contralateral tumors, when distant radiotherapy was combined with either anti-PD1 or anti-CD137 mAb.…”

Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy

“…Investigators have been exploring combination strategies in order to enhance the overall efficacy of these novel treatment strategies while limiting the toxicity. Indeed, a number of studies have explored the combination of an OV with checkpoint blockade in cancer models3435363738, and ongoing clinical trials are addressing this. These studies have demonstrated that viral infection overcomes tumour resistance to immune checkpoint blockade immunotherapy3639.…”

Efficient expression of bioactive murine IL12 as a self-processing P2A polypeptide driven by inflammation-regulated promoters in tumor cell lines

“…7 Nevertheless, despite these results, IL12 remains as a recognized anticancer agent with a great potential for synergistic combinations with other immunotherapies and/or conventional cancer treatments. 37,38 Finally, there is increasing evidence showing the importance of host responses to viral vectors for successful experimental cancer therapies. There is evidence of IL12 and IFN interplay in the control of tumor growth.…”