Expression of IFN-β enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma

Candice L. Willmon, Vassiliki Saloura, Zvi G. Fridlender, Phonphimon Wongthida, Rosa Maria Diaz, Jill Thompson, Timothy Kottke, Mark Federspiel, Glen Barber, Steven M. Albelda, Richard G. Vile

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69 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7713-7720
Number of pages8
JournalCancer Research
Volume69
Issue number19
DOIs
StatePublished - Oct 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Willmon, C. L., Saloura, V., Fridlender, Z. G., Wongthida, P., Diaz, R. M., Thompson, J., Kottke, T., Federspiel, M., Barber, G., Albelda, S. M., & Vile, R. G. (2009). Expression of IFN-β enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma. Cancer Research, 69(19), 7713-7720. https://doi.org/10.1158/0008-5472.CAN-09-1013