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Eradication of Solid Human Breast Tumors in Nude Mice with an Intravenously Injected Light-Emitting Oncolytic Vaccinia Virus

¹ Genelux Corporation, San Diego Science Center, San Diego, California; ² Immunogenetics Laboratory, Department of Transfusion Medicine; ³ Functional Genomics and Proteomics Facility, Critical Care Medicine Department, Clinical Center; ⁴ Mathematical and Statistical Computing Laboratory, Division of Computational Bioscience, Center for Information Technology, NIH, Bethesda, Maryland; and ⁵ Virchow Center for Experimental Biomedicine, Institute for Biochemistry and Institute for Molecular Infection Biology, University of Würzburg, Am Hubland, Würzburg, Germany

Requests for reprints: Aladar A. Szalay, Genelux Corporation, San Diego Science Center, 3030 Bunker Hill Street, San Diego, CA 92109. Phone: 858-483-0024; Fax: 858-483-0025; E-mail: aaszalay{at}genelux.com.

Previously, we reported that a recombinant vaccinia virus (VACV) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. A new recombinant VACV, GLV-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding Renilla luciferase–Aequorea green fluorescent protein fusion, ß-galactosidase, and ß-glucuronidase) into the F14.5L, J2R (encoding thymidine kinase) and A56R (encoding hemagglutinin) loci of the viral genome, respectively. I.v. injections of GLV-1h68 (1 x 10⁷ plaque-forming unit per mouse) into nude mice with established (300–500 mm³) s.c. GI-101A human breast tumors were used to evaluate its toxicity, tumor targeting specificity, and oncolytic efficacy. GLV-1h68 showed an enhanced tumor targeting specificity and much reduced toxicity compared with its parental LIVP strains. The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus–mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of IFN-stimulated genes (STAT-1 and IRF-7), cytokines, chemokines, and innate immune effector function. These findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. [Cancer Res 2007;67(20):10038–46]

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