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Effective Therapy of Metastatic Ovarian Cancer with an Oncolytic Herpes Simplex Virus Incorporating Two Membrane Fusion Mechanisms¹

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030 [M. N., X. F., F. M., A. J., L. T., X. Z.], and The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [R. C. B.]

Purpose and Experimental Design: Replication-competent herpes simplex virus [HSV (oncolytic HSV)] holds considerable promise for treating malignant solid tumors, although the potency of the virus needs improvement if its full clinical potential is to be realized. Incorporation of membrane fusion capability into an oncolytic HSV, either by screening for a syncytial HSV mutant after random mutagenesis or by inserting a hyperfusogenic glycoprotein from gibbon ape leukemia virus into the viral genome, can significantly enhance the antitumor effects of the virus (X. Fu and X. Zhang, Cancer Res., 62: 2306–2312, 2002; X. Fu et al., Mol. Ther., in press, 2003). We reasoned that both fusogenic strategies, incorporated into a single oncolytic HSV, might significantly improve virotherapy for ovarian cancer.

Results: In vitro characterization of a doubly fusogenic oncolytic HSV (Synco-2D) showed that this virus produces a distinctive syncytial phenotype, leading to a significantly increased tumor cell killing ability, compared with that of a nonfusogenic virus. When injected directly into the abdominal cavity of mice bearing human ovarian cancer xenografts, Synco-2D eradicated all tumor masses in 75% of the animals, whereas no animals in the conventional oncolytic HSV-treated group were tumor free.

Conclusions: This newly generated fusogenic oncolytic HSV is a promising candidate for clinical testing against advanced ovarian cancer.

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