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Expression of IFN-β Enhances Both Efficacy and Safety of Oncolytic Vesicular Stomatitis Virus for Therapy of Mesothelioma

Departments of ¹ Molecular Medicine and ² Immunology, Mayo Clinic, Rochester, Minnesota; ³ Thoracic Oncology Research Laboratory, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and ⁴ Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida

Requests for reprints: Richard G. Vile, Mayo Clinic, Guggenheim 18, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-3178; Fax: 507-266-2122; E-mail: vile.richard{at}mayo.edu.

Key Words: VSV • IFN-β • mesothelioma • oncolytic virotherapy

Our preclinical and clinical trials using a replication-defective adenoviral vector expressing IFN-β have shown promising results for the treatment of malignant mesothelioma. Based on the hypotheses that a replication-competent vesicular stomatitis virus (VSV) oncolytic vector would transduce more tumor cells in vivo, that coexpression of the immunostimulatory IFN-β gene would enhance the immune-based effector mechanisms associated both with regression of mesotheliomas and with VSV-mediated virotherapy, and that virus-derived IFN-β would add further safety to the VSV platform, we tested the use of IFN-β as a therapeutic transgene expressed from VSV as a novel treatment for mesothelioma. VSV-IFN-β showed significant therapy against AB12 murine mesotheliomas in the context of both local and locoregional viral delivery. Biologically active IFN-β expressed from VSV added significantly to therapy compared with VSV alone, dependent in part on host CD8⁺ T-cell responses. Immune monitoring suggested that these antitumor T-cell responses may be due to a generalized T-cell activation rather than the priming of tumor antigen–specific T-cell responses. Finally, IFN-β also added considerable extra safety to the virus by providing protection from off-target viral replication in nontumor tissues and protected severe combined immunodeficient mice from developing lethal neurotoxicity. The enhanced therapeutic index provided by the addition of IFN-β to VSV therefore provides a powerful justification for the development of this virus for future clinical trials. [Cancer Res 2009;69(19):7713–20]