Zentralbl Gynakol 2005; 127 - A35
DOI: 10.1055/s-2005-921026

Gene Therapy for ovarian cancer via a novel fiber modified conditionally replicating Adenovirus

DT Rein 1, M Breidenbach 2, GJ Bauerschmitz 1, DM Nettelbeck 3, DT Curiel 4, P Dall 1
  • 1Department of Obstetrics and Gynecology, University of Düsseldorf Medical Center, Düsseldorf, Germany
  • 2Department of Obstetrics and Gynecology, University of Aachen Medical Center, Aachen, Germany
  • 3Department of Dermatology, University of Erlangen-Nürnberg, Erlangen, Germany
  • 4Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama, USA

Conditionally replicating adenoviruses (CRADs) are a novel approach for treatment of cancer. The oncolytic potency of CRADs is determined by their capability to infect tumor cells. Unfortunately, expression of the primary receptor for Ad5 is highly variable on ovarian cancer cells. Genetic fiber pseudotyping is an approach to circumvent this problem by using the alternative Ad serotype 3 receptor for entry into, and killing of ovarian cancer cells. Furthermore, restriction of the CRAD replication to tumor cells minimizes nontumor tissue injury. In this study, we constructed a fiber-modified CRAD containing the secretory leukoprotease inhibitor (SLPI) promoter to control viral replication via the E1A gene (Ad5/3SLPI). SLPI has been shown to be over-expressed in various tumors including ovarian cancer but minimally active in normal tissues. Viral replication and oncolysis were assessed in various ovarian cancer cell lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell sheroids purified from fresh patient samples. Moreover, in a therapeutic orthotopic mouse model of peritoneal carcinomatosis, dramatically enhanced survival was noted with Ad5/3SLPI. To assess the selectivity of Ad5/3SLPI we evaluated the ability of the viruses to replicate in non-target liver cells in vivo. Liver pathology and viral E1A RNA levels were evaluated 48 hours after i.v. injection of viruses into immunocompetent mice. Little to no hepatotoxicity was seen with the non replicative E1-deleted vector whereas pronounced effects were seen with the replication competent Ad5/3wt vector. In summary, Ad5/3SLPI is a promising candidate for treating metastatic ovarian cancer and showed robust virus replication, oncolysis, and in vivo therapeutic efficacy. Ad5/3SLPI showed comparatively low liver toxicity and therefore holds great potential for clinical testing.

Eingereicht von: Daniel T. Rein

d.rein@gmx.de