title: Model-based rational design of an oncolytic virus with improved therapeutic potential.
abstract: Oncolytic viruses are complex biological agents that interact at multiple levels with both tumour and normal tissues. Antiviral pathways induced by interferon are known to have a critical role in determining tumour cell sensitivity and normal cell resistance to infection with oncolytic viruses. Here we pursue a synthetic biology approach to identify methods that enhance antitumour activity of oncolytic viruses through suppression of interferon signalling. On the basis of the mathematical analysis of multiple strategies, we hypothesize that a positive feedback loop, established by virus-mediated expression of a soluble interferon-binding decoy receptor, increases tumour cytotoxicity without compromising normal cells. Oncolytic rhabdoviruses engineered to express a secreted interferon antagonist have improved oncolytic potential in cellular cancer models, and display improved therapeutic potential in tumour-bearing mice. Our results demonstrate the potential of this methodology in evaluating potential caveats of viral immune-evasion strategies and improving the design oncolytic viruses.
authors.affiliation: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Le Bœuf
authors.forename: Cory
authors.initials: C
authors.lastname: Batenchuk
authors.forename: Markus
authors.initials: M
authors.lastname: Vähä-Koskela
authors.forename: Sophie
authors.initials: S
authors.lastname: Breton
authors.forename: Dominic
authors.initials: D
authors.lastname: Roy
authors.forename: Chantal
authors.initials: C
authors.lastname: Lemay
authors.forename: Julie
authors.initials: J
authors.lastname: Cox
authors.forename: Hesham
authors.initials: H
authors.lastname: Abdelbary
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.forename: Girija
authors.initials: G
authors.lastname: Waghray
authors.forename: Harold
authors.initials: H
authors.lastname: Atkins
authors.forename: David
authors.initials: D
authors.lastname: Stojdl
authors.forename: Jean-Simon
authors.initials: JS
authors.lastname: Diallo
authors.forename: Mads
authors.initials: M
authors.lastname: Kærn
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
mesh_terms: D000818:Animals; D016923:Cell Death; D003198:Computer Simulation; D005840:Gentian Violet; D057131:Immune Evasion; D007372:Interferons / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D015203:Reproducibility of Results; D012209:Rhabdoviridae / Q000502:physiology; D014018:Tissue Distribution; D014779:Virus Replication
chemical_list: D007372:Interferons; D005840:Gentian Violet