Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963
Steve H. Thorne, … , John Bell, David H. Kirn
Steve H. Thorne, … , John Bell, David H. Kirn
Published October 25, 2007
Citation Information: J Clin Invest. 2007;117(11):3350-3358. https://doi.org/10.1172/JCI32727.
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Research Article Oncology

Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963

Abstract

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.

Authors

Steve H. Thorne, Tae-Ho H. Hwang, William E. O’Gorman, David L. Bartlett, Shizuko Sei, Femina Kanji, Christopher Brown, Joel Werier, Jin-Han Cho, Dong-Ewon Lee, Yaohe Wang, John Bell, David H. Kirn

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Figure 2

Systemic delivery of viral strains to tumors.

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Systemic delivery of viral strains to tumors. 1 × 109 PFU of vaccinia st...
1 × 109 PFU of vaccinia strain WR or Ad5 were delivered i.v. to immuno­competent mice bearing subcutaneous CMT 64 or JC tumors (both lines susceptible to replication by both viruses after intratumoral injection). Mice were sacrificed after 48 or 72 hours or after 10 days and immunohistochemistry performed against viral coat proteins on paraffin-embedded sections of tumor tissue. (A) Graphs show scoring of positive cells in each tumor (asterisk indicates none detectable). For each condition, results are based on tumors from 3 mice, and for each tumor, 10 randomly chosen fields of view were scored. (B) Representative photographs show sections at 72 hours and 10 days after treatment (original magnification, ×100).