The use of oncolytic virus VSVΔ51 as a novel therapeutic strategy in pancreatic cancer

Abstract : Context As of 2020, Pancreatic Cancer is the 3rd leading cause of cancer-related deaths in Canada. The most common subtype of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which accounts for approximately 90% of all pancreatic cancer cases diagnosed every year. Limited therapeutic strategies are available to patients. Standard of Care (SOC) for PDAC patients has remained unchanged in the last three decades. Gemcitabine remains the backbone of therapy for most patients. However, the efficacy of SOC is limited as multiple factors in PDAC contribute to therapeutic resistance. The tumour microenvironment (TME) in PDAC is known to be fibrotic and immunologically cold. To better target and eradicate cancer cells, more specific therapies such as oncolytic viruses have been developed to improve patient outcome. Oncolytic viruses such as VSVΔ51, will specifically replicate in the cancer cells. VSVΔ51also has the ability to lyse cancer cells and induce immunogenic cell death (ICD). The release of damage associated molecular patterns (DAMPs) from the dying PDAC cells will lead to a tumour specific immune response. Hypothesis PDAC therapy could be improved by the induction of ICD through the addition of the oncolytic virus VSVΔ51to SOC gemcitabine. Objectives The objectives are to characterize the immune-targeting effects of VSVΔ51 following PDAC cell lines and combine VSVΔ51 with SOC gemcitabine to evaluate the potential synergy of the therapies. Methods The evaluation of both the cytotoxic and replication abilities of VSVΔ51 in PDAC cell lines were done. To evaluate cell viability following infection, MTT assays were performed. To evaluate replication, viral plaque assays were done. Additionally, the release of DAMPs (HSP90, HMGB1) was also measured, by Western Blot to ensure the induction of ICD. The cell viability following the combination of gemcitabine and VSVΔ51was also measured, by crystal violet staining as well as the DAMP release (HSP70, HSP90, and HMGB1) by Western Blot. Results Our results demonstrate that VSVΔ51 is functional and is able to infect, lyse and replicate amongst PDAC cells. VSVΔ51 on its own is able to induce the release of DAMPs. We have also demonstrated that VSVΔ51 in combination with gemcitabine is able to induce cell death and release DAMPs as well Conclusion VSVΔ51 presents a novel more specific potential therapeutic strategy for PDAC. VSVΔ51 can be used in combination with current SOC to further eradicate cancer cells.

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