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Simple Summary: Cancer immunotherapy has evolved rapidly in the last decade. A newly emerging immunotherapeutic approach utilizes oncolytic viruses to enhance the ability of the body's own immune system to recognize and clear tumor cells. We have recently developed a novel chimeric oncolytic virus and demonstrated its anti-tumoral effects in various preclinical mouse models. To gain mechanistic insights into the immune response to this form of therapy at the cellular level and to identify targets to potentially further improve the therapy, we analyzed the immune cell signature in the tumors, blood, and lymphoid tissue in a syngeneic melanoma mouse model by flow cytometry. Both local and systemic immune responses were observed. Furthermore, selective depletion of cytotoxic T cells indicated that these cells are the main players in mediating the therapeutic response to this novel virotherapy. Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8+ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8+ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer immunotherapy involves the application of strategies aimed at enhancing the body's immune system to recognize and clear tumor cells. One such immunotherapeutic approach utilizes cytotoxic immune cells (T cells) harvested from the patient, which are expanded and activated, followed by re-infusion to the same patient. This process is termed adoptive cell therapy (ACT). Although effective in a limited setting, efforts are being made to improve these therapies through the development of rationally designed combination treatments. We have developed an approach, whereby tumors are pretreated with a virus, which has oncolytic effects on the tumor cells, in addition to modulating changes in the tumor microenvironment, thereby improving the recruitment of the adoptively transferred cytotoxic T cells and resulting in synergistic therapeutic responses in the tumor. This results in a substantial prolongation of survival, as demonstrated in an immune-competent mouse model of melanoma. Cancer immunotherapies have made major advancements in recent years and are becoming the prevalent treatment options for numerous tumor entities. However, substantial response rates have only been observed in specific subsets of patients since pre-existing factors determine the susceptibility of a tumor to these therapies. The development of approaches that can actively induce an anti-tumor immune response, such as adoptive cell transfer and oncolytic virotherapy, have shown clinical success in the treatment of leukemia and melanoma, respectively. Based on the immune-stimulatory capacity of oncolytic VSV-NDV virotherapy, we envisioned a combination approach to synergize with adoptive T cell transfer, in order to enhance tumor cell killing. Using the immune-competent B16 melanoma model, we demonstrate that combination treatment has beneficial effects on the suppressive microenvironment through upregulation of MHC-I and maintaining low expression levels of PD-L1 on tumor cells. The approach led to additive cytotoxic effects and improved the recruitment of T cells to virus-infected tumor cells in vitro and in vivo. We observed substantial delays in tumor growth and evidence of abscopal effects, as well as prolongation of overall survival time when administered at clinically relevant dosing conditions. Our results indicate that treatment with oncolytic VSV-NDV, combined with adoptive T cell therapy, induces multi-mechanistic and synergistic tumor responses, which supports the further development of this promising translational approach. [ABSTRACT FROM AUTHOR]