Myxoma Virus Expressing LIGHT (TNFSF14) Pre-Loaded into Adipose-Derived Mesenchymal Stem Cells Is Effective Treatment for Murine Pancreatic Adenocarcinoma.

Abstract

Simple SummaryPancreatic cancer is a deadly disease with no effective therapy. Oncolytic viruses such as myxoma (MYXV) have revealed great potential to treat malignancies, due to dual anti-cancer effects—oncolytic and immune-stimulating effects. We aimed to verify whether adipose-derived mesenchymal stem cells (ADSCs) pre-loaded ex vivo with transgene-armed myxoma construct would be useful for transferring the virus to murine pancreatic lesions and whether this would reduce tumor burden. We confirmed that the carrier cells remained viable after infection, in contrast to pancreatic cancer cells, which were destroyed. Intraperitoneal (IP) administration of the shielded virus (ADSCs/MYXV) revealed localization in the pancreas, decreased tumor burden and an adaptive anti-tumor immune response. We conclude that ADSCs pre-loaded with recombinant MYXV and administered IP allowed for the ferrying of the virus to pancreatic cancer lesions, followed by tumor regression and extended survival in the treated mice. This therapeutic approach has excellent potential for treating pancreatic cancer.Pancreatic ductal adenocarcinoma (PDAC) is a weakly immunogenic fatal neoplasm. Oncolytic viruses with dual anti-cancer properties—oncolytic and immune response-boosting effects—have great potential for PDAC management. Adipose-derived stem cells (ADSCs) of mesenchymal origin were infected ex vivo with recombinant myxoma virus (MYXV), which encodes murine LIGHT, also called tumor necrosis factor ligand superfamily member 14 (TNFSF14). The viability and proliferation of ADSCs were not remarkably decreased (1–2 days) following MYXV infection, in sharp contrast to cells of pancreatic carcinoma lines studied, which were rapidly killed by the infection. Comparison of the intraperitoneal (IP) vs. the intravenous (IV) route of ADSC/MYXV administration revealed more pancreas-targeted distribution of the virus when ADSCs were delivered IP to mice bearing orthotopically injected PDAC. The biodistribution, tumor burden reduction and anti-tumor adaptive immune response were examined. Bioluminescence data, used to assess the presence of the luciferase-tagged virus after IP injection, indicated enhanced trafficking into the pancreata of mice bearing orthotopically-induced PDAC, as compared to tumor-free animals, resulting in extended survival of the treated PDAC-seeded animals and in the boosted expression of key adaptive immune response markers. We conclude that ADSCs pre-loaded with transgene-armed MYXV and administered IP allow for the effective ferrying of the oncolytic virus to sites of PDAC and mediate improved tumor regression.