Experimental Evolution Generates Novel Oncolytic Vesicular Stomatitis Viruses with Improved Replication in Virus-Resistant Pancreatic Cancer Cells

Author:

Seegers Sara L.1,Frasier Connor1,Greene Sarah1,Nesmelova Irina V.2,Grdzelishvili Valery Z.1

Affiliation:

1. Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, USA

2. Department of Physics and Optical Science, University of North Carolina at Charlotte, Charlotte, North Carolina, USA

Abstract

Vesicular stomatitis virus (VSV)-based oncolytic viruses are promising agents against pancreatic ductal adenocarcinoma (PDAC). However, some PDAC cell lines are resistant to VSV. Here, using a directed viral evolution approach, we generated novel oncolytic VSVs with an improved ability to replicate in virus-resistant PDAC cell lines, while remaining highly attenuated in nonmalignant cells. Two independently evolved VSVs obtained 2 identical VSV glycoprotein mutations, K174E and E238K. Additional experiments indicated that these acquired G mutations improved VSV replication, at least in part due to improved virus attachment to SUIT-2 cells. Importantly, no deletions or mutations were found in the virus-carried transgenes in any of the passaged viruses. Our findings demonstrate long-term genomic stability of complex VSV recombinants carrying large transgenes and support further clinical development of oncolytic VSV recombinants as safe therapeutics for cancer.

Funder

HHS | NIH | National Cancer Institute

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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