Expression of IFN-beta enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma.
Our preclinical and clinical trials using a replication-defective adenoviral vector expressing IFN-beta 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-beta gene would enhance the immune-based effector mechanisms associated both with regression of mesotheliomas and with VSV-mediated virotherapy, and that virus-derived IFN-beta would add further safety to the VSV platform, we tested the use of IFN-beta as a therapeutic transgene expressed from VSV as a novel treatment for mesothelioma. VSV-IFN-beta showed significant therapy against AB12 murine mesotheliomas in the context of both local and locoregional viral delivery. Biologically active IFN-beta 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-beta 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-beta to VSV therefore provides a powerful justification for the development of this virus for future clinical trials.
Willmon
Candice L
CL
Departments of Molecular Medicine and Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Saloura
Vassiliki
V
Fridlender
Zvi G
ZG
Wongthida
Phonphimon
P
Diaz
Rosa Maria
RM
Thompson
Jill
J
Kottke
Timothy
T
Federspiel
Mark
M
Barber
Glen
G
Albelda
Steven M
SM
Vile
Richard G
RG
D000818:Animals; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D008654:Mesothelioma / Q000235:genetics / Q000276:immunology / Q000628:therapy* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009422:Nervous System Diseases / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods*; D013601:T-Lymphocytes / Q000276:immunology; D018116:Vesiculovirus / Q000235:genetics*
D018984:Epitopes, T-Lymphocyte; D016899:Interferon-beta