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Oncolytic Vesicular Stomatitis Viruses Are Potent Agents for Intravesical Treatment of High-Risk Bladder Cancer

¹ The Prostate Centre at Vancouver General Hospital, Departments of ² Urologic Sciences and ³ Surgery, and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada; and ⁴ Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, Ontario, Canada

Requests for reprints: Paul S. Rennie, The Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6. Phone: 604-875-4818; Fax: 604-875-5654; E-mail: paul.rennie{at}vch.ca.

Key Words: Bladder cancer • Intravesical therapy • Oncolytic vesicular stomatitis virus • Orthotopic mouse model • Bioluminescence imaging

Bladder cancer is the second most common genitourinary malignancy. At initial diagnosis, 70% of cases are non–muscle-invasive; however, current treatment options for superficial disease are of limited efficacy because many patients will develop recurrent tumors. The purpose of this study was to examine two replication-competent oncolytic vesicular stomatitis virus (VSV) strains as intravesical agents in an orthotopic murine model of high-grade bladder cancer. Four human bladder cancer cell lines (RT4, MGH-U3, UM-UC3, and KU-7) were treated with either wild-type VSV or a mutant 51M variant (AV3) in vitro. Both wild-type VSV and AV3, which has an impaired ability to shutdown innate immunity, preferentially killed the more aggressive, IFN-nonresponsive cell lines UM-UC3 and KU-7, whereas IFN-responsive RT4 and MGH-U3 cells were less susceptible. In vivo, KU-7-luc bladder tumor cells, which stably express firefly luciferase, were inoculated into nude mice by intravesical instillation and tumor growth was quantified using bioluminescence imaging. Mice with established xenografts were administered VSV intravesically on days 4, 9, and 14, and necropsy was performed after 3 weeks. AV3 as well as wild-type VSV significantly inhibited KU-7-luc tumor growth by 90% (AV3) and 98% (wild-type), respectively, as compared with controls treated with UV-inactivated VSV. Despite using immunocompromised hosts, there was no evidence of toxicity in either group. In conclusion, VSV instillation therapy showed promising antitumor activity and safety in an orthotopic model of bladder cancer. These findings provide preclinical proof-of-principle for the intravesical use of VSV against non–muscle-invasive bladder cancer, especially in IFN-refractory patients. [Cancer Res 2008;68(12):4506–10]

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