Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus

Anna Kanerva, Kurt R. Zinn, Tandra R. Chaudhuri, John T. Lam, Kaori Suzuki, Taco G. Uil, Tanja Hakkarainen, Gerd J. Bauerschmitz, Minghui Wang, Bin Liu, Zhihong Cao, Ronald D. Alvarez, David T. Curiel, Akseli Hemminki

Research output: Contribution to journalArticlepeer-review

149 Scopus citations

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-Δ24, 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-Δ24 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-Δ24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-Δ24 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.

Original languageEnglish
Pages (from-to)449-458
Number of pages10
JournalMolecular Therapy
Volume8
Issue number3
DOIs
StatePublished - Sep 1 2003

Keywords

  • Adenovirus
  • Biological therapy
  • Gene therapy
  • Ovarian neoplasms
  • Virus replication

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