Abstract

Oncolytic Vaccinia Vectors for Cancer Immunotherapy

Takafumi Nakamura, Associate Professor, Division of Molecular Medicine, Tottori University

Vaccinia virus, once widely used for smallpox vaccine, has been genetically engineered and used as an oncolytic virus for cancer virotherapy. The therapeutic index is successfully enhanced by stricter tumor-specific viral replication, stronger oncolytic potency, and optimized induction of antitumor immunity. Two viral proteins VGF and O1 contribute to viral replication and spread by activation of EGFR-dependent MAPK/ERK pathway. VGF- and O1-deleted vaccinia virus (MDRVV) inhibited pathogenic viral replication in normal cells without impairing therapeutic replication in tumor cells. Recently, fusogenic vaccinia virus (FUVAC) was discovered during plaque purification of the MDRVV. FUVAC has a nonsense mutation in the viral gene K2L, whereas other viral genomes are maintained in the MDRVV. Using a bilaterally tumor-bearing syngeneic mouse model, unilateral administration of FUVAC more efficiently enhanced CD8+ T cell infiltration and inhibited tumor growth in not only treated tumors but also untreated tumors than MDRVV. Interestingly, FUVAC reduced tumor-associated immune suppressive cells such as regulatory T cells, myeloid-derived suppressor cells and tumor-associated macrophages in the injected tumor. In accordance with the change for the better, the anticancer effects of FUVAC in both injected and non-injected tumors were completely suppressed by depletion of CD8+ T cells. Taken together, fusogenic vaccinia virus exerts more potent antitumor immune responses by modulating the tumor microenvironment than non-fusogenic vaccinia virus. Furthermore, the simultaneous expression of immune-modulating genes in FUVAC augmented the antitumor activity via inducing potent and durable antitumor immune responses following viral oncolysis. The combined properties have the potential to overcome oncolytic virus-resistant tumors which limit the clinical benefits due to tumor heterogeneity and the complexity of tumor microenvironment. Thus, FUVAC would be better therapeutic platform as a next-generation oncolytic vaccinia vector.