Model-based rational design of an oncolytic virus with improved therapeutic potential

Fabrice Le Bœuf, Cory Batenchuk, Markus Vähä-Koskela, Sophie Breton, Dominic Roy, Chantal Lemay, Julie Cox, Hesham Abdelbary, Theresa Falls, Girija Waghray, Harold Atkins, David Stojdl, Jean-Simon Diallo, Mads Kærn and John C. Bell ()
Additional contact information
Fabrice Le Bœuf: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Cory Batenchuk: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Markus Vähä-Koskela: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Sophie Breton: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Dominic Roy: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Chantal Lemay: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Julie Cox: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Hesham Abdelbary: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Theresa Falls: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Girija Waghray: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Harold Atkins: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
David Stojdl: Apoptosis Research Center, Children’s Hospital of Eastern Ontario
Jean-Simon Diallo: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute
Mads Kærn: Ottawa Institute of Systems Biology, University of Ottawa
John C. Bell: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2974

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