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. 2015 May;3(5):449-54.
doi: 10.1158/2326-6066.CIR-14-0216. Epub 2015 Feb 17.

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

José I Quetglas  1 , Sara Labiano  2 , M Ángela Aznar  2 , Elixabet Bolaños  2 , Arantza Azpilikueta  2 , Inmaculada Rodriguez  2 , Erkuden Casales  2 , Alfonso R Sánchez-Paulete  2 , Víctor Segura  2 , Cristian Smerdou  2 , Ignacio Melero  1
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Virotherapy with a Semliki Forest Virus-Based Vector Encoding IL12 Synergizes with PD-1/PD-L1 Blockade

José I Quetglas et al. Cancer Immunol Res. 2015 May.

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 + 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 IFNγ-dependent fashion. PD-L1-mediated adaptive resistance thereby provides a mechanistic explanation of the observed synergistic effects achieved by the SFV-IL12 + anti-PD-1 mAb combination.

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