Deletion of immunomodulatory genes as a novel approach to oncolytic vaccinia virus development

Molecular Therapy: Oncolytics

David F. Stojdl¹  Lili Okamoto²  J. Andrea McCart³  Tiffany Y. Ho³  David Mealiea³ 

[1] Corresponding author: Dave Mealiea, Toronto General Hospital Research Institute, University Health Network, 280 Elizabeth Street, Toronto, ON M5G 2C4, Canada.;Department of Surgery, University of Toronto, Stewart Building, 149 College Street, Toronto, ON M5T 1P5, Canada;Toronto General Hospital Research Institute, University Health Network, 280 Elizabeth Street, Toronto, ON M5G 2C4, Canada;

关键词: oncolytic virus;    virotherapy;    immunotherapy;    cancer therapy;    oncology;    virology;   

DOI  :  

来源: DOAJ

【 摘 要 】

Vaccinia virus (VV) has emerged as a promising platform for oncolytic virotherapy. Many clinical VV candidates, such as the double-deleted VV, vvDD, are engineered with deletions that enhance viral tumor selectivity based on cellular proliferation rates. An alternative approach is to exploit the dampened interferon-based innate immune responses of tumor cells by deleting one of the many VV immunomodulatory genes expressed to dismantle the antiviral response. We hypothesized that such a VV mutant would be attenuated in non-tumor cells but retain the ability to effectively propagate in and kill tumor cells, yielding a tumor-selective oncolytic VV with significant anti-tumor potency. In this study, we demonstrated that VVs with a deletion in one of several VV immunomodulatory genes (N1L, K1L, K3L, A46R, or A52R) have similar or improved in vitro replication, spread, and cytotoxicity in colon and ovarian cancer cells compared to vvDD. These deletion mutants are tumor selective, and the best performing candidates (ΔK1L, ΔA46R, and ΔA52R VV) are associated with significant improvement in survival, as well as immunomodulation, within the tumor environment. Overall, we show that exploiting the diminished antiviral responses in tumors serves as an effective strategy for generating tumor-selective and potent oncolytic VVs, with important implications in future oncolytic virus (OV) design.

【 授权许可】

Unknown