Oncolytic Viruses: Now Interviewing for the All-Star Game
Authors: Richard Vile
Journal: Molecular Therapy (2010)

With the start of the 2010 soccer World Cup imminent, things are a little tense at home. My son, born and bred in the United States, wears his “USA” jersey every day. In retaliation, I wear a replica of the jersey worn by the English team that gloriously won the World Cup in 1966. Our problem is that the United States will play England in June—and one of us is going to be sulking for some time to follow. Recently, we suggested in these pages1Pandha H Melcher A Harrington K Vile R Oncolytic viruses: time to compare, contrast, and combine? 5th International Meeting on Replicating Oncolytic Virus Therapeutics. Banff, Alberta, Canada, 18–22 March 2009.Mol Ther. 2009; 17: 934-935Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar that it would be timely to set up the World Cup of Oncolytic Viruses to compare at least some of the multiple different viruses now being investigated as potential cancer therapeutics. In this way, it might be possible to understand more clearly what properties are likely to be most important going forward to clinical trials. One of the many obstacles to such comparative studies is that, as among the dedicated followers of sports teams the world over, much passion is engendered by the partisanship that accompanies support for one particular team—or virus. You have only to listen to ardent supporters of any team (or, indeed, virus) to appreciate how such partisanship often results in at least a partial suspension of objectivity. The USA-versus-England matchup should, however, be quite a game. The English game is built largely on a solid, bruising defense, while the US team has its strength in attack (http://news.bbc.co.uk/sport2/hi/football/world_cup_2010/default.stm). While contemplating our impending family rift, my son recently made the observation that a team with the English defense combined with an American attack would produce a much stronger unit than either alone. A similar philosophy—combination rather than competition—has now been applied to the field of oncolytic virotherapy for the first time, as reported by Le Boeuf et al. in this issue.2Le Boeuf F Diallo J-S McCart JA Thorne S Falls T Stanford M et al.Synergistic interaction between oncolytic viruses augments tumor killing.Mol Ther. 2010; 18: 888-895Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar One of the many ways in which to group the large variety of oncolytic viruses currently on the market3Cattaneo R Miest T Shashkova EV Barry MA Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded.Nat Rev Microbiol. 2008; 6: 529-540Crossref PubMed Scopus (305) Google Scholar is by the extent to which they encode genes that can influence the host response to the viral infection.4Mulhern O Harrington B Bowie AG Modulation of innate immune signalling pathways by viral proteins.Adv Exp Med Biol. 2009; 666: 49-63Crossref PubMed Scopus (14) Google Scholar For example, in general terms, larger viruses tend to encode multiple proteins that inhibit the innate immune response to infection. This contrasts with smaller viruses, which rely more heavily upon a rapid “slash and burn” strategy to outpace the innate antiviral immune response (Figure 1a,b). Le Boeuf and colleagues exploited these two strategies—of “combine and conquer”—in order to enhance the efficacy of tumor oncolysis. They combined the defensive expertise of an oncolytic vaccinia virus (VV),5McCart JA Ward JM Lee J Hu Y Alexander HR Libutti SK et al.Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes.Cancer Res. 2001; 61: 8751-8757PubMed Google Scholar which expresses multiple immune-deflecting genes, with the quick-fire, aggressive attacking qualities of the vesicular stomatitis virus (VSV).6Stojdl DF Lichty BD Knowles S Marius R Atkins H Sonenberg N et al.Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.Nat Med. 2000; 6: 821-825Crossref PubMed Scopus (665) Google Scholar,7Stojdl DF Lichty BD tenOever BR Paterson JM Power AT Knowles S et al.VSV strains with defects in their ability to shut down innate immunity are potent systemic anti-cancer agents.Cancer Cell. 2003; 4: 263-275Abstract Full Text Full Text PDF PubMed Scopus (665) Google Scholar In cultured tumor cells, they demonstrated that a prior dose of oncolytic VV very efficiently “softened up” the tumor cell population, so that a subsequent infection by VSV led to complete cell killing—even in cell lines that are otherwise rather resistant to the cytotoxic effects of VSV. Enhanced oncolysis correlated with increases of up to 1,000-fold in viral titers compared with cells infected with VSV alone, and true synergy was observed in the doubly infected cultures. Interestingly, using viruses tagged with different colors, synergy was shown to result from a preconditioning effect by VV infection that led to increased susceptibility of the whole culture for VSV infection/replication/killing. The VV genome is large, encoding multiple proteins that interfere with, deflect, or inhibit the host innate immune responses to infection.8Perdiguero B Esteban M The interferon system and vaccinia virus evasion mechanisms.J Interferon Cytokine Res. 2009; 29: 581-598Crossref PubMed Scopus (130) Google Scholar Therefore there are many candidate VV-produced factors that might lead to this preconditioning effect for enhanced VSV replication.9Zeh HJ Bartlett DL Development of a replication-selective, oncolytic-poxvirus for the treatment of human cancers.Cancer Gene Ther. 2002; 9: 1001-1012Crossref PubMed Scopus (89) Google Scholar Following what must have been some relatively painstaking scouting for the best players for this role, Le Boeuf et al. identified the VV B18R gene product as at least one of the principal central defenders used by VV to nullify the host immune response. Thus, a VV deprived of B18R was unable to sensitize tumor cultures maximally to VSV infection, and supernatants from tumor cells infected by the B18R-defective VV could not transfer sensitization effectively to new tumor cultures. Finally, recombinant B18R was able to confer increased sensitivity to VSV infection even in the absence of VV. B18R counteracts the type I interferon (IFN) response that is generated upon viral infection of both normal and tumor cells.10Colamonici OR Domanski P Sweitzer SM Larner A Buller RM Vaccinia virus B18R gene encodes a type I interferon-binding protein that blocks interferon alpha transmembrane signaling.J Biol Chem. 1995; 270: 15974-15978Crossref PubMed Scopus (260) Google Scholar Consistent with its role in enhancing sensitivity to VSV replication by interfering with the antiviral IFN response, the addition of IFN-α inhibited the effects of B18R on target cells. These data combine persuasively to suggest a model in which VV infection induces viral proteins that rapidly nullify the type I IFN cellular response to that infection (Figure 1b). By sending VSV into the game at just the right moment, this model can exploit the VV-induced blockade of the IFN response, which would otherwise inhibit VSV infection (Figure 1c). The result is rapid goal scoring by VSV (viral replication, propagation, and tumor cell killing) before the host immune response can catch up. VV and VSV can not only play well together at home in the culture dish, in vitro, but also “on the road,” in vivo. Intravenous delivery of VSV, at levels that had no therapeutic effects against tumors alone, became effective following prior administration of VV. Moreover, these effects were highly restricted to the tumor as opposed to other organs, where viral replication would generate unwanted toxicity. These studies suggest that the combination of tumor-selective oncolytic viruses may allow both for the use of lower doses of each virus alone and for the generation of an effectively tumor-specific oncolytic team. For the icing on the cake, Le Boeuf and colleagues took the virological equivalent of the “you scratch my back, I'll scratch yours” principle one step further to show that it is not only VV that can facilitate VSV replication. They constructed a VSV encoding a protein that induces the fusion of infected cells (VSVFAST).11Brown CW Stephenson KB Hanson S Kucharczyk M Duncan R Bell JC et al.The p14 FAST protein of reptilian reovirus increases vesicular stomatitis virus neuropathogenesis.J Virol. 2009; 83: 552-561Crossref PubMed Scopus (51) Google Scholar Coinfection of VV with VSVFAST led to increased cell fusion, resulting in increased release of intracellular VV; these levels of VV spread and induced replication in excess of 100-fold compared with the levels generated by coinfection with VSV alone. This is the first report of a study combining two diverse oncolytic viruses to generate increased overall oncolytic potency.2Le Boeuf F Diallo J-S McCart JA Thorne S Falls T Stanford M et al.Synergistic interaction between oncolytic viruses augments tumor killing.Mol Ther. 2010; 18: 888-895Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar There will undoubtedly be many more. The potential for mixing and matching is enormous and represents another positive application for the many different candidate oncolytic viruses being reported. However, there are also concerns. For example, many sports provide a season-ending “all stars” game, in which the best of the best are brought together from different individual teams. However, such games often lack the excitement and quality of matches between real clubs. One problem is that the players are not well adapted to or familiar with each other. The end result is a level of performance well below that of the individual clubs from which the players come. Similarly, it is likely that many combinations of viruses will not generate the synergy seen between VV and VSV—and may even result in significant levels of interference and reduced efficacy. However, the highest-profile concern is the specter of recombination between different viruses to generate a novel, highly pathogenic, pandemic-inducing virus. In the current study,2Le Boeuf F Diallo J-S McCart JA Thorne S Falls T Stanford M et al.Synergistic interaction between oncolytic viruses augments tumor killing.Mol Ther. 2010; 18: 888-895Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar the choice of combining partners—a large DNA virus with a small RNA virus—was directed in part specifically to reducing the chances of recombination. Nonetheless, no specific testing was done to ensure that no such recombination had occurred—although exactly what would be tested for and how to prove the complete absence of such species is a tricky problem that future studies will have to grapple with. The release of major Hollywood blockbusters such as I Am Legend, in which a man-made, potentially cancer-curing virus goes catastrophically out of control, will not help in this regard. In addition, anyone who has tried to go through the regulatory authorities to the clinic with even a single oncolytic virus will recoil in trepidation at repeating the process with two. And it may be best not even to raise the issues of financial burdens and intellectual-property concerns imposed on such a trial by the need to license and make two different viruses to the appropriate clinical grade. The English and US soccer teams will not be combining into a single World Cup squad anytime soon, which bodes ill for relations between father and son in the Vile household. However, with the publication of this article,2Le Boeuf F Diallo J-S McCart JA Thorne S Falls T Stanford M et al.Synergistic interaction between oncolytic viruses augments tumor killing.Mol Ther. 2010; 18: 888-895Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar it is highly probable that individual players from different virotherapy teams will be brought together to try out as potential all-star combinations. This promises to generate a new era of novel viro-combination therapies—to complement the established paradigms already used in chemo- and radio-combination therapies for cancer. In addition, it also may be that the promise of improved potency through combination will fortuitously provide a much more palatable route for comparison along the way!