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A Fiber-Modified Mesothelin Promoter–Based Conditionally Replicating Adenovirus for Treatment of Ovarian Cancer

Authors' Affiliations: ¹ Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Pathology, Surgery, and The Gene Therapy Center; ² Departments of Obstetrics and Gynecology; and ³ Departments of Pathology, Cell Biology and Surgery, The University of Alabama at Birmingham, Birmingham, Alabama; ⁴ Department of Obstetrics and Gynecology, Rhine-Westphalian Technical University, Aachen, Germany; ⁵ Departments of Gynecology and Obstetrics, University of Düsseldorf Medical Center, Düsseldorf, Germany; ⁶ Department of Biochemistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and ⁷ Departments of Pathology, Neurosurgery and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York

Requests for reprints: David T. Curiel, Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Pathology, and Surgery, and The Gene Therapy Center, The University of Alabama at Birmingham, 901 19th Street South, BMR2-508, Birmingham, AL 35294-2180. Phone: 205-934-8627; Fax: 205-975-7476; E-mail: curiel{at}uab.edu.

Purpose: Recently, virotherapy has been proposed as a new therapeutic approach for ovarian cancer. Conditionally replicative adenoviruses (CRAd) may contain tumor-specific promoters that restrict virus replication to cancer cells. Mesothelin, a cell surface glycoprotein, is overexpressed in ovarian cancer but not in normal ovarian tissues. The purpose of this study was to explore the therapeutic utility of a mesothelin promoter–based CRAd in a murine model of ovarian cancer, using noninvasive in vivo imaging.

Experimental Design: We constructed a mesothelin promoter–based CRAd with a chimeric Ad5/3 fiber (AdMSLNCRAd5/3) that contains an Ad5 tail, Ad5 shaft, and an Ad3 knob. Previously, a chimeric Ad5/3 fiber has shown improved infectivity in many ovarian cancer cells. Viral replication and oncolysis were assessed in a panel of ovarian cancer cell lines. To test the oncolytic efficacy of AdMSLNCRAd5/3 in a murine model, bioluminescence imaging of tumor luciferase activity and survival analysis were done.

Results: AdMSLNCRAd5/3 achieved up to a 10,000-fold higher cell killing effect and up to 120-fold higher levels of viral replication in all human ovarian cancer cells, compared with wild-type Ad5. AdMSLNCRAd5/3 significantly inhibited tumor growth as confirmed by in vivo imaging (P < 0.05). Survival with AdMSLNCRAd5/3 was significantly enhanced when compared with no virus or with a wild-type Ad5-treated group (P < 0.05).

Conclusions: The robust replication, oncolysis, and in vivo therapeutic efficacy of AdMSLNCRAd5/3 showed that this CRAd is a promising candidate for treating ovarian cancer. Importantly, we have applied in vivo imaging that has allowed repeated and longitudinal measurements of tumor growth after CRAd treatment.