Cytokine-modified VSV is attenuated for neural pathology, but is both highly immunogenic and oncolytic

James Miller¹, Sarah M Bidula^1,2, Troels M Jensen^1,3, Carol Shoshkes Reiss^1,4

¹Department of Biology, New York University, New York, NY, USA; ²Present address: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; ³Present address: New York School of Medicine, New York, NY, USA; ⁴Center for Neural Science, NYU Cancer Institute and Microbiology Department, School of Medicine, New York University, New York, NY, USA

Abstract: Vesicular stomatitis virus (VSV), an enveloped, nonsegmented, negative-stranded RNA virus, is being tested by several laboratories as an antitumor agent. Unfortunately, viral infection of the central nervous system (CNS) has been observed by many groups following administration to tumor-bearing animals. In rodents, VSV encephalitis is characterized by weight-loss, paralysis, and high mortality. In order to provide protection from VSV infection of the CNS after therapeutic administration, we have attenuated VSV by the introduction of the gene encoding the proinflammatory cytokine interleukin (IL)-23, and designated the new virus VSV23. We hypothesize that while VSV23 is replicating within tumors, resulting in tumor destruction, the expression of IL-23 will enhance host antitumor and antiviral immune responses. In the event that the virus escapes from the tumor, the host’s immune system will be activated and the virus will be rapidly cleared from healthy tissue. Experimental VSV23 infection of the CNS is characterized by decreased viral replication, morbidity, and mortality. VSV23 is capable of stimulating the enhanced production of nitric oxide in the CNS, which is critical for elimination of VSV from infected neurons. Intraperitoneal administration of VSV23 stimulates both nonspecific natural killer cell, virus-specific cytolytic T lymphocyte and memory virus-specific proliferative T cell responses against wild-type VSV in splenocytes. Furthermore, VSV23 is able to replicate in, and induce apoptosis of tumor cells in vitro. These data indicate that VSV23 is immunogenic, attenuated and suitable for testing as an efficacious and safe oncolytic agent.

Keywords: IL-23, oncolytic, tumor, VSV