title: Re-engineering vesicular stomatitis virus to abrogate neurotoxicity, circumvent humoral immunity, and enhance oncolytic potency.
abstract: As cancer treatment tools, oncolytic viruses (OV) have yet to realize what some see as their ultimate clinical potential. In this study, we have engineered a chimeric vesicular stomatitis virus (VSV) that is devoid of its natural neurotoxicity while retaining potent oncolytic activity. The envelope glycoprotein (G) of VSV was replaced with a variant glycoprotein of the lymphocytic choriomeningitis virus (LCMV-GP), creating a replicating therapeutic, rVSV(GP), that is benign in normal brain but can effectively eliminate brain cancer in multiple preclinical tumor models in vivo. Furthermore, it can be safely administered systemically to mice and displays greater potency against a spectrum of human cancer cell lines than current OV candidates. Remarkably, rVSV(GP) escapes humoral immunity, thus, for the first time, allowing repeated systemic OV application without loss of therapeutic efficacy. Taken together, rVSV(GP) offers a considerably improved OV platform that lacks several of the major drawbacks that have limited the clinical potential of this technology to date.
authors.affiliation: Authors' Affiliations: Georg-Speyer-Haus, Frankfurt am Main, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Muik
authors.affiliation: Ottawa Hospital Research Institute, Centre for Innovative Cancer Research;
authors.forename: Lawton J
authors.initials: LJ
authors.lastname: Stubbert
authors.affiliation: Department of Biomedicine, University of Bergen;
authors.forename: Roza Z
authors.initials: RZ
authors.lastname: Jahedi
authors.affiliation: Authors' Affiliations: Georg-Speyer-Haus, Frankfurt am Main, Germany;
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Geiβ
authors.affiliation: Institute for Virology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Janine
authors.initials: J
authors.lastname: Kimpel
authors.affiliation: Institute for Virology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dold
authors.affiliation: Institute for Virology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Tober
authors.affiliation: Authors' Affiliations: Georg-Speyer-Haus, Frankfurt am Main, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Volk
authors.affiliation: Ottawa Hospital Research Institute, Centre for Innovative Cancer Research;
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Authors' Affiliations: Georg-Speyer-Haus, Frankfurt am Main, Germany;
authors.forename: Ursula
authors.initials: U
authors.lastname: Dietrich
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada;
authors.forename: Beta
authors.initials: B
authors.lastname: Yadollahi
authors.affiliation: Ottawa Hospital Research Institute, Centre for Innovative Cancer Research;
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.affiliation: Department of Biomedicine, University of Bergen; Department of Pathology, Haukeland University Hospital, Bergen, Norway; and.
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada;
authors.forename: David
authors.initials: D
authors.lastname: Stojdl
authors.affiliation: Ottawa Hospital Research Institute, Centre for Innovative Cancer Research;
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.affiliation: Institute for Virology, Innsbruck Medical University, Innsbruck, Austria dorothee.von-Laer@i-med.ac.at.
authors.forename: Dorothee
authors.initials: D
authors.lastname: von Laer
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D000956:Antigens, Viral / Q000235:genetics*; D045744:Cell Line, Tumor; D006224:Cricetinae; D005260:Female; D005822:Genetic Vectors; D005909:Glioblastoma / Q000628:therapy*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D057131:Immune Evasion; D056724:Immunity, Humoral; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000009:adverse effects*; D050504:Oncolytic Viruses / Q000235:genetics*; D015202:Protein Engineering; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics*; D014759:Viral Envelope Proteins / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D000912:Antibodies, Neoplasm; D000914:Antibodies, Viral; D000956:Antigens, Viral; C028391:G protein, vesicular stomatitis virus; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C115679:glycoprotein peptide, Lymphocytic choriomeningitis virus