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

Abstract

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.

PRO-Simat: Protein network simulation and design tool

“…Vaccinia virus proved to be a robust synthetic biology tool to implement different oncolysis designs. This includes new therapeutic options even for challenging cancers such as pancreatic cancer [85] or lung cancer [86] . To better analyse the latter, PRO-Simat has included lung adenocarcinoma gene expression data.…”

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

“…Another noteworthy combination regimen is oncolytic virus immunotherapy. Oncolytic vaccinia virus mpJX-594 combined with the PD-1 antibody can induce an extensive influx of cytotoxic T cells into tumor tissues, inhibit tumor proliferation, and subside liver metastasis, thereby increasing survival time in pancreatic NET mice models [ 123 ].…”

An Extensive Review on Preclinical and Clinical Trials of Oncolytic Viruses Therapy for Pancreatic Cancer

“…( 190 ) investigated the efficiency of vaccinia virus mpJX-594 (mpJX) in combination with anti-programmed death receptor-1 antibody (aPD1) in pancreatic neuroendocrine tumors (PanNETs). The aPD1 and mpJX activate the elevated antitumor immune response in mice models, with an increased level of apoptosis and reduced proliferation ( 191 ).…”