title: Application of interferon modulators to overcome partial resistance of human ovarian cancers to VSV-GP oncolytic viral therapy.
abstract: Previously, we described an oncolytic vesicular stomatitis virus variant pseudotyped with the nonneurotropic glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, which was highly effective in glioblastoma. Here, we tested its potency for the treatment of ovarian cancer, a leading cause of death from gynecological malignancies. Effective oncolytic activity of VSV-GP could be demonstrated in ovarian cancer cell lines and xenografts in mice; however, remission was temporary in most mice. Analysis of the innate immune response revealed that ovarian cancer cell lines were able to respond to and produce type I interferon, inducing an antiviral state upon virus infection. This is in stark contrast to published data for other cancer cell lines, which were mostly found to be interferon incompetent. We showed thatin vitrothis antiviral state could be reverted by combining VSV-GP with the JAK1/2-inhibitor ruxolitinib. In addition, for the first time, we report thein vivoenhancement of oncolytic virus treatment by ruxolitinib, both in subcutaneous as well as in orthotopic xenograft mouse models, without causing significant additional toxicity. In conclusion, VSV-GP has the potential to be a potent and safe oncolytic virus to treat ovarian cancer, especially when combined with an inhibitor of the interferon response.
authors.affiliation: Division of Virology, Medical University of Innsbruck , Innsbruck, Austria.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dold
authors.affiliation: Division of Virology, Medical University of Innsbruck , Innsbruck, Austria.
authors.forename: Carles
authors.initials: C
authors.lastname: Rodriguez Urbiola
authors.affiliation: Division of Virology, Medical University of Innsbruck , Innsbruck, Austria.
authors.forename: Guido
authors.initials: G
authors.lastname: Wollmann
authors.affiliation: Division of Virology, Medical University of Innsbruck , Innsbruck, Austria.
authors.forename: Lisa
authors.initials: L
authors.lastname: Egerer
authors.affiliation: Applied Virology and Gene Therapy Unit , Frankfurt am Main, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Muik
authors.affiliation: Division of Virology, Medical University of Innsbruck , Innsbruck, Austria.
authors.forename: Lydia
authors.initials: L
authors.lastname: Bellmann
authors.affiliation: Department of Gynecology and Obstetrics, Medical University of Innsbruck , Innsbruck, Austria.
authors.forename: Heidelinde
authors.initials: H
authors.lastname: Fiegl
authors.affiliation: Department of Gynecology and Obstetrics, Medical University of Innsbruck , Innsbruck, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Marth
authors.affiliation: Division of Virology, Medical University of Innsbruck , Innsbruck, Austria.
authors.forename: Janine
authors.initials: J
authors.lastname: Kimpel
authors.affiliation: Division of Virology, Medical University of Innsbruck , Innsbruck, Austria.
authors.forename: Dorothee
authors.initials: D
authors.lastname: von Laer