Feola et al. showed that their peptide-loaded oncolytic vaccine, PeptiCRAd, in combination with anti-PD-L1 therapy was effective in both B16.OVA melanoma and 4TI triple-negative breast cancer murine models. In the B16.OVA model, combination therapy improved median survival, generated complete responses, and showed a significant increase in activated (but not exhausted) OVA-specific CD8+ TILs. In the 4T1 model, targeting both MHC-I and -II was more effective in limiting tumor growth; PeptiCRAd I+II combined with anti-PD-L1 increased CD8+ TILs and reduced CD4+ TILs.

Activation of immune checkpoint pathways and limited T- cell infiltration result in immunological escape of tumors. Although immune checkpoint inhibitors are currently approved for several types of cancers, the response rate is often limited by the lack of tumor specific T-cells within the malignant tissue. Therefore, new combinatorial strategies are needed to enhance the clinical benefit of immune checkpoint inhibitors. We have previously developed PeptiCRAd, an oncolytic vaccine platform capable of directing the immune response toward tumor epitopes. In this study, we evaluated whether the platform could be used to increase the response rate to checkpoint inhibitors in both highly immunogenic and poorly immunogenic tumors, such as melanoma and triple negative breast cancer (TNBC). We report here that anti-PD-L1 therapy in combination with PeptiCRAd significantly reduced the growth of melanomas and increased the response rate to checkpoint inhibition. In fact, we registered a higher rate of complete responses among mice treated with the combination. This approach promoted the presence of non-exhausted antigen-specific T-cells within the tumor in comparison to anti-PD-L1 monotherapy. Furthermore, we found that targeting both MHC-I and II restricted tumor epitopes was necessary to decrease the growth of the poorly immunogenic TNBC model 4T1 and that combination with PD-L1 blockade increased the number of responders to checkpoint inhibition. Finally, the described strategy was validated in a translational in vitro model using HLA matched human PBMCs and tumor cell lines. Consistent to our previous results, improved cytotoxicity was observed with combination of PeptiCRAd and anti-PD-L1. These results demonstrate that oncolytic virus based cancer vaccine can significantly improve the response rate to checkpoint blocking antibodies in the context of immunogenic and non-immunogenic tumors.

Author Info: (1) Dipartamento di Medicina Molecolare e Biotecnologie Mediche, Universita di Napoli Federico II, Via Pansini 5, Naples, Italy; (2) (3) (4) (5) (9) (10) Laboratory

Author Info: (1) Dipartamento di Medicina Molecolare e Biotecnologie Mediche, Universita di Napoli Federico II, Via Pansini 5, Naples, Italy; (2) (3) (4) (5) (9) (10) Laboratory of Immunovirotherapy, Drug Research Doctoral Peogram, University of Helsinki, Helsinki, Finland; (6) Department of pharmaceutical and pharmacological sciences, University of Padova, Via F. Marzolo 5, Padova, Italy; (7) University of Pisa, Lungarno Antonio Pacinotti, Pisa, Italy; (8) University of Siena, via Aldo Moro 2, Siena, Italy; (11) Dipartamento di Medicina Molecolare e Biotecnologie Mediche, Universita di Napoli Federico II, Via Pansini 5, Naples, Italy and Helsinki Institute of Life Science, HILIFE, University of Helsinki, Finland (12) Laboratory of Immunovirotherapy, Drug Research Doctoral Program, University of Helsinki, Helsinki, Finland and Helsinki Institute of Life Science, HILIFE, University of Helsinki, Finland.

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