Efficacy of Systemically Administered Mutant Vesicular Stomatitis Virus (VSV{Delta}51) Combined with Radiation for Nasopharyngeal Carcinoma

doi:10.1158/1078-0432.CCR-07-4134

Cancer Therapy: Preclinical

Efficacy of Systemically Administered Mutant Vesicular Stomatitis Virus (VSV ${Delta}$ 51) Combined with Radiation for Nasopharyngeal Carcinoma

Nehad M. Alajez¹^,2, Joseph D. Mocanu¹^,2, Wei Shi¹^,2, Marie C. Chia¹^,2, Caroline J. Breitbach⁷^,8, Angela B.Y. Hui¹^,2, Shane Knowles⁸, John C. Bell⁷^,8, Pierre Busson⁹, Kenzo Takada¹⁰, Kwok-Wai Lo¹¹, Brian O'Sullivan³^,5, Pat Gullane⁴^,6 and Fei-Fei Liu¹^,2^,3^,4^,5

Authors' Affiliations: ¹ Division of Applied Molecular Oncology, Ontario Cancer Institute; Departments of ² Medical Biophysics, ³ Radiation Oncology, and ⁴ Otolaryngology, University of Toronto; Departments of ⁵ Radiation Oncology and ⁶ Surgical Oncology, University Health Network, Toronto, Ontario, Canada; ⁷ Centre for Cancer Therapeutics, Ottawa Health Research Institute; ⁸ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada; ⁹ Institut Gustave Roussy, Villejuif, France; ¹⁰ Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; ¹¹ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, People's Republic of China

Requests for reprints: Fei-Fei Liu, Department of Radiation Oncology, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2123; Fax: 416-946-4586; E-mail: Fei-Fei.Liu{at}rmp.uhn.on.ca.

Purpose: Nasopharyngeal carcinoma (NPC) is a malignancy of thehead and neck region that is associated with EBV latency. Curativetreatments for NPC achieve modest survival rates, underscoringa need to develop novel therapies. We evaluated the therapeuticpotential of a mutant vesicular stomatitis virus (VSV ${Delta}$ 51) assingle treatment modality or in combination with ionizing radiation(RT) in NPC.

Experimental Design: MTS assay was used to assess cell viabilityin vitro; apoptosis was measured using propidium iodide stainingand caspase activation. In vivo experiments were conducted usingtumor-bearing nude mice with or without local RT (4 Gy). Apoptosiswas assessed in excised tumor sections with terminal deoxynucleotidyltransferase–mediated dUTP nick end labeling staining.

Results: Our data showed that NPC cells are exquisitely sensitiveto VSV ${Delta}$ 51 oncolysis, which correlated with the presence of EBV.Efficacy of VSV ${Delta}$ 51 against NPC cells was further augmented whencombined with RT. A single systemic injection of VSV ${Delta}$ 51 achieved50% survival in treated mice, which increased to 83% when combinedwith local tumor RT. In addition to induction of apoptosis,an antiangiogenic effect of VSV ${Delta}$ 51 was observed in vivo, suggestinga novel tumoricidal mechanism for VSV ${Delta}$ 51. This virus also preventedgrowth of NPC sphere-forming cells in vitro, showing potentialutility in targeting NPC-initiating cells.

Conclusions: Our data represent the first report showing thatEBV-positive NPC cells are exquisitely sensitive to VSV ${Delta}$ 51 oncolysisand documenting the successful utilization of this combinatorialregimen as a novel curative therapeutic strategy for NPC.