Replication-selective oncolytic viruses (virotherapeutics) are being developed as novel
cancer therapies with unique mechanisms of action, but limitations in i.v. delivery to
tumors and systemic efficacy have highlighted the need for improved agents for this therapeutic class to realize its potential. Here we describe the rational, stepwise design and evaluation of a systemically effective virotherapeutic (JX-963). We first identified a highly potent poxvirus strain that also trafficked efficiently to human
tumors after i.v. administration. This strain was then engineered to target
cancer cells with activation of the
transcription factor E2F and the EGFR pathway by deletion of the
thymidine kinase and
vaccinia growth factor genes. For induction of
tumor-specific cytotoxic T lymphocytes, we further engineered the virus to express human
GM-CSF. JX-963 was more potent than the previously used virotherapeutic
Onyx-015 adenovirus and as potent as wild-type
vaccinia in all
cancer cell lines tested. Significant
cancer selectivity of JX-963 was demonstrated in vitro in human tumor cell lines, in vivo in
tumor-bearing rabbits, and in primary human surgical samples ex vivo.
Intravenous administration led to systemic efficacy against both primary
carcinomas and widespread organ-based
metastases in immunocompetent mice and rabbits. JX-963 therefore holds promise as a rationally designed, targeted virotherapeutic for the systemic treatment of
cancer in humans and warrants clinical testing.