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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

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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 6

Intravenous delivery and tumor selectivity of vvDD versus wild-type vaccinia (WR).

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Intravenous delivery and tumor selectivity of vvDD versus wild-type vacc...
(A) Biodistribution of WR and vvDD following systemic delivery to tumor-bearing mice. Athymic CD1 nu/nu mice bearing subcutaneous human HCT 116 tumors (arrows) were treated with 1 × 107 PFU of vaccinia strains via tail vein injection. Viral strains (WR and vvDD) expressed luciferase, and the subsequent biodistribution of viral gene expression was detected by bioluminescence imaging in an IVIS 100 system (Xenogen; Caliper Life Sciences) following addition of the substrate luciferin at the times indicated after treatment. Representative mice from n = 5/group are shown; the remaining mice are shown in Supplemental Figure 6. (B) Viral gene expression, as quantified by light production, was plotted over time for the regions of interest covering the whole body (ventral image) (dashed line, open symbols) or from the tumor only (dorsal view, region of interest over tumor) (solid line, filled symbols) for BALB/c mice bearing subcutaneous JC tumors (n = 5 mice/group) and treated with 1 × 107 PFU of either virus by tail vein injection. (C) Recovery of vvDD delivered systemically (i.p. injection of 1 × 109 PFU) to C57BL/6 mice bearing subcutaneous MC38 tumors. Mice were sacrificed on days 5 or 8 after treatment (n = 8/group), different tissues recovered, and viral infectious units (PFU/mg tissue) titered by plaque assay (asterisk indicates below the limits of detection).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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