1. ¹Division of Human Gene Therapy, Department of Medicine, Department of Pathology, and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
2. ²Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
3. ³Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama, USA
4. ⁴Rational Drug Design, Biomedicum, University of Helsinki, Finland
5. ⁵Department of Oncology, Helsinki University Central Hospital, 00014 Helsinki, Finland
6. ⁶Department of Surgery, Helsinki University Central Hospital–Jorvi Hospital, Espoo, Finland
7. ⁷Molecular Medicine Program, Mayo Clinic and Foundation, Rochester, Minnesota
8. ⁸Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
9. ⁹Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland

Correspondence: Akseli Hemminki, Cancer Gene Therapy Group, Rational Drug Design, Biomedicum Helsinki, Department of Oncology, Helsinki University Central Hospital, P.O. Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland. Fax: +358-9-1912 5155. E-mail: Akseli.Hemminki@Helsinki.fi.

Received 9 April 2003; Accepted 25 May 2003.

Abstract

Oncolytic viruses that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. However, the oncolytic potency of replicating agents is determined directly by their capability of infecting target cells. Most adenoviruses used for gene therapy or virotherapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 (the coxsackie–adenovirus receptor, or CAR) is highly variable on ovarian and other cancer cells. By performing genetic fiber pseudotyping, we created Ad5/3-24, a conditionally replicating adenovirus that does not bind CAR but facilitates entry into and killing of ovarian cancer cells. We show replication of Ad5/3-24 and subsequent oncolysis of ovarian adenocarcinoma lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell spheroids purified from patient samples. Moreover, in a therapeutic orthotopic model of peritoneal carcinomatosis, dramatically enhanced survival was noted. Finally, Ad5/3-24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-24 is improved over the respective CAR- and integrin-binding controls. Taken together with promising biodistribution and toxicity data, this approach could translate into successful clinical interventions for ovarian cancer patients.