Oncolytic Virus With Attributes of Vesicular Stomatitis Virus and Measles Virus in Hepatobiliary and Pancreatic Cancers

Nagalo, Bolni Marius; Breton, Camilo Ayala; Zhou, Yumei; Arora, Mansi; Bogenberger, James M.; Barro, Oumar; Steele, Michael B.; Jenks, Nathan J.; Baker, Alexander T.; Duda, Dan G.; Roberts, Lewis Rowland; Russell, Stephen J.; Peng, Kah Whye; Borad, Mitesh J.

Abstract Recombinant vesicular stomatitis virus (VSV)-fusion and hemagglutinin (FH) was developed by substituting the promiscuous VSV-G glycoprotein (G) gene in the backbone of VSV with genes encoding for the measles virus envelope proteins F and H. Hybrid VSV-FH exhibited a multifaceted mechanism of cancer-cell killing, and improved neurotolerability over parental VSV in preclinical studies. In this study, we evaluated VSV-FH in vitro and in vivo in models of hepatobiliary and pancreatic cancers. Our results indicate that high intrahepatic doses of VSV-FH did not result in any significant toxicity and were well tolerated by transgenic mice expressing the measles virus receptor CD46. Furthermore, single intratumoral treatments with VSV-FH yielded improved survival and complete tumor regressions in a proportion of mice in the Hep3B hepatocellular carcinoma model, but not in mice xenografted with BxPC3 pancreatic cancer cells. Our preliminary findings indicate that VSV-FH can induce potent oncolysis in hepatocellular and pancreatic cancer cell lines with concordant results in vivo in hepatocellular cancer and discordant in pancreatic cancer, without the VSV-mediated toxic effects previously observed in laboratory animals. Further study of VSV-FH as an oncolytic virotherapy is warranted in hepatocellular carcinoma and pancreatic cancer, to understand broader applicability and mechanisms of sensitivity and resistance.