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A novel chimeric oncolytic virus vector for improved safety and efficacy in hepatocellular carcinoma.

J Virol. 2018 Sep 19. pii: JVI.01386-18. doi: 10.1128/JVI.01386-18. [Epub ahead of print]

Authors/Editors: Abdullahi S, Jäkel M, Behrend SJ, Steiger K, Topping G, Krabbe T, Colombo A, Sandig V, Schiergens TS, Thasler WE, Werner J, Lichtenthaler SF, Schmid RM, Ebert O, Altomonte J.
Publication Date: 2018

10_abdullahi

Abstract

Oncolytic viruses represent an exciting new aspect of the evolving field of cancer immunotherapy. We have engineered a novel hybrid vector comprising vesicular stomatitis virus (VSV) and Newcastle disease virus (NDV), named rVSV-NDV, wherein the VSV backbone is conserved, but its glycoprotein has been replaced by the hemagglutinin-neuraminidase (HN) and the modified, hyperfusogenic fusion (F) envelope proteins of recombinant NDV. As opposed to wild-type VSV, which kills cells through a classical cytopathic effect, the recombinant virus is able to induce tumor-specific syncytia formation, allowing for efficient cell-to-cell spread of the virus and a rapid onset of immunogenic cell death. Furthermore, the glycoprotein exchange substantially abrogates the off-target effects in brain and liver tissue associated with wildtype VSV, resulting in a substantially enhanced safety profile, even in immune-deficient NOD-SCID mice which are highly susceptible to wild-type VSV. Although NDV causes severe pathogenicity in its natural avian hosts, the incorporation of the envelope proteins in the chimeric rVSV-NDV vector is avirulent in embryonated chicken eggs. Finally, systemic administration of rVSV-NDV in orthotopic HCC-bearing immune-competent mice resulted in significant survival prolongation. This strategy, therefore, combines the beneficial properties of the rapidly replicating VSV platform with the highly efficient spread and immunogenic cell death of a fusogenic virus, without risking the safety and environmental threats associated with either parental vector. Taken together, rVSV-NDV represents an attractive vector platform for clinical translation as a safe and effective oncolytic virus.Importance The therapeutic efficacy of oncolytic viral therapy often comes as a trade-off with safety, such that potent vectors are often associated with toxicity, while safer viruses tend to have attenuated therapeutic effects. Despite promising preclinical data, the development of VSV as a clinical agent has been substantially hampered by the fact that severe neuro- and hepatotoxicity have been observed in rodents and nonhuman primates in response to treatment with wild-type VSV. Although NDV has been shown to have an attractive safety profile in humans with promising oncolytic effects, its further development has been severely restricted due to the environmental risks it poses. The hybrid rVSV-NDV vector, therefore, represents an extremely promising vector platform in that it has been rationally designed to be safe, both to the recipient and the environment, while being simultaneously effective, both through its direct oncolytic actions and via induction of immunogenic cell death.

 

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