NATURAL KILLER T CELL IMMUNOTHERAPY IN COMBINATION WITH RECOMBINANT ONCOLYTIC VESICULAR STOMATITIS VIRUS AND IMMUNE CHECKPOINT THERAPY REDUCES TUMOR BURDEN IN MODELS OF PANCREATIC AND BREAST CANCER

Abstract

Cancer is the leading cause of death in Canada. Current treatments, such as chemotherapy and radiation, have high rates of adverse effects leading to dose-limiting toxicities and reduced therapeutic efficacy. Therefore, new treatments that are safe and effective are needed. I examined natural killer T (NKT) cell therapy in combination with recombinant oncolytic vesicular stomatitis virus (VSV-ΔM51) expressing the cytokine IL-15 (VSV-IL-15) or reovirus fusion associated small transmembrane (FAST) proteins in models of pancreatic and metastatic breast cancer, respectively. In the pancreatic model, VSV-IL-15 in combination with NKT cell immunotherapy increased tumor regression and overall survival. The addition of anti-PD-1 to the combination treatment further enhanced tumor immune infiltration, cytotoxicity, and cytokine production, resulting in 20% of mice experiencing complete tumor regression. Combination of VSV-ΔM51 expressing the FAST proteins p14 (VSV-p14) or p15 (VSV-p15) with NKT cell therapy led to 100% survival in the metastatic breast cancer model. In both models, combined therapy enhanced tumor regression and increased survival time over individual treatments and was superior to NKT cell therapy combined with VSV-ΔM51 expressing green fluorescent protein (VSV-GFP). Combination treatments increased tumor immune infiltration, cytotoxic activity, and proinflammatory cytokine production, to mediate increased tumor control. In both models, mice who survived initial tumor challenged had slower tumor growth compared to naïve mice upon rechallenge, demonstrating formation of immune memory. Therefore, combined NKT cell immunotherapy, with VSV-IL-15, VSV-p14, or VSV-p15, presents a promising treatment strategy for pancreatic and metastatic breast cancer, respectively.