Oncolytic ImmunoViroTherapy: A long history of crosstalk between viruses and immune system for cancer treatment.

Cancer Immunotherapy relies on harnessing a patient's immune system to fine-tune specific anti-tumor responses and ultimately eradicate cancer. Among diverse therapeutic approaches, oncolytic viruses (OVs) have emerged as a novel form of cancer immunotherapy. OVs are a naturally occurring or genetically modified class of viruses able to selectively kill cancer cells, leaving healthy cells unharmed; in the last two decades, the role of OVs has been redefined to act beyond their oncolytic activity. Indeed, the immunogenic cancer cell death mediated by OVs induces the release of tumor antigens that in turn induces anti-tumor immunity, allowing OVs to act as in situ therapeutic cancer vaccines. Additionally, OVs can be engineered for intratumoral delivery of immunostimulatory molecules such as tumor antigens or cytokines to further enhance anti-tumor response. Moreover, OVs can be used in combination with other cancer immunotherapeutic approaches such as Immune Checkpoint Inhibitors and CAR-T cells. The current review first defines the three main mechanisms of action (MOA) of OVs currently used in cancer therapy that are: i) Oncolysis, ii) OV-induced cancer-specific immune activation, and iii) Exploiting pre-existing anti-viral immunity to enhance cancer therapy. Secondly, we focus on how OVs can induce and/or improve anti-cancer immunity in a specific or unspecific fashion, highlighting the importance of these approaches. Finally, the last part of the review analyses OVs combined with other cancer immunotherapies, revising present and future clinical applications.

Oncolytic vaccines increase the response to PD-L1 blockade in immunogenic and poorly immunogenic tumors.

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.