A novel chimeric oncolytic virus vector for improved safety and efficacy as a platform for the treatment of hepatocellular carcinoma

Sarah Abdullahi, Melanie Jäkel, Sabine J. Behrend, Katja Steiger, Geoffrey Topping, Teresa Krabbe, Alessio Colombo, Volker Sandig, Tobias S. Schiergens, Wolfgang E. Thasler, Jens Werner, Stefan F. Lichtenthaler, Roland M. Schmid, Oliver Ebert, Jennifer Altomonte

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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virus (NDV), named recombinant VSV-NDV (rVSV-NDV), wherein the VSV backbone is conserved but its glycoprotein has been replaced by the hemagglutinin-neuraminidase (HN) and the modified, hyperfusogenic fusion (F) envelope proteins of recombinant NDV. In comparison to wild-type VSV, which kills cells through a classical cytopathic effect, the recombinant virus is able to induce tumor-specific syncytium formation, allowing 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 wild-type VSV, resulting in a markedly enhanced safety profile, even in immune-deficient NOD.CB17-prkdc scid /NCrCrl (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 hepatocellular carcinoma (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. Taking the data together, rVSV-NDV represents an attractive vector platform for clinical translation as a safe and effective oncolytic virus.

Original languageEnglish
Article numbere01386
JournalJournal of Virology
Volume92
Issue number23
DOIs
StatePublished - 2018

Keywords

  • Chimeric virsu
  • Fusion protein
  • Hepatocellular carcinoma
  • Immunotherapy
  • Oncolytic virus
  • Syncytia

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