Virotherapy With A Semliki Forest Virus-Based Vector Encoding Il-12 Synergizes With Pd-1/Pd-L1 Blockade

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAVirotherapy 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.Citation Format: Jose I. Quetglas, Sara Labiano, M. Angela Aznar, Elixabet Bolanos, Arantza Azpilicueta, Inmaculada Rodriguez, Erkuden Casales, Alfonso Rodriguez, Cristian Smerdou, Ignacio Melero. Virotherapy with a Semliki Forest virus-based vector encoding IL-12 synergizes with PD-1/PD-L1 blockade. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 281. doi:10.1158/1538-7445.AM2015-281