Oncolytic vaccinia virus injected intravenously sensitizes pancreatic neuroendocrine tumors and metastases to immune checkpoint blockade.

This study determined the influence of intravenous (i.v.) oncolytic vaccinia virus mpJX-594 (mpJX) on antitumor activity of anti-programmed death receptor-1 antibody (aPD1) in functional and metastatic pancreatic neuroendocrine tumors (PanNETs). One i.v. dose of mpJX, engineered for mice with the same plasmid design as clinical virus Pexa-Vec, was administered alone or with repeated dosing of aPD1 (mpJX+aPD1) to two contrasting genetic models of PanNET: one developing benign insulin-secreting tumors (RIP1-Tag2;C57BL/6J mice) and the other developing liver metastases (RIP1-Tag2;AB6F1 mice). Experiments revealed that aPD1 had synergistic actions with mpJX on CD8 T cell and natural killer (NK) cell influx, apoptosis, and suppression of proliferation in PanNETs. After mpJX+aPD1, the 53-fold increase in apoptosis (5 days) and 85% reduction in proliferation (20 days) exceeded the sum of mpJX and aPD1 given separately. mpJX+aPD1 also stabilized blood insulin and glucose in mice with functional PanNETs, regressed liver metastases in mice with aggressive PanNETs, and prolonged survival of both. The findings revealed that mpJX+aPD1 converted "cold" PanNETs into immunogenic tumors with widespread cytotoxic T cell influx, tumor cell killing, and suppression of proliferation. Reduction of tumor insulin secretion from functional PanNETs prolonged survival, and anti-metastatic actions on aggressive PanNETs reduced the metastatic burden to less than before treatment. The findings support the efficacy of the vaccinia virus with aPD1 for functional and metastatic PanNETs.