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

• Published in: Nature communications Vol. 4; no. 1; p. 1974
• Main Authors: Le Bœuf, Fabrice, Batenchuk, Cory, Vähä-Koskela, Markus, Breton, Sophie, Roy, Dominic, Lemay, Chantal, Cox, Julie, Abdelbary, Hesham, Falls, Theresa, Waghray, Girija, Atkins, Harold, Stojdl, David, Diallo, Jean-Simon, Kærn, Mads, Bell, John C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2013; Nature Publishing Group
• Subjects: 631/553; 692/308; 692/699/67/1059; 692/700/565/1331; Animals; Cell Death; Computer Simulation; Cytotoxicity; Gentian Violet; Humanities and Social Sciences; Immune Evasion; Interferons - metabolism; Mice; Mice, Inbred BALB C; Models, Biological; multidisciplinary; Oncolytic Virotherapy; Oncolytic Viruses - physiology; Reproducibility of Results; Rhabdoviridae - physiology; Science; Science (multidisciplinary); Tissue Distribution; Tumors; Virus Replication
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2974

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. Oncolytic viruses can serve as self-replicating anticancer agents. Le Bœuf et al . combine synthetic modelling and molecular biology approaches to create a virus with enhanced oncolytic activity in vitro and in vivo due to its expression of an interferon antagonist.