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Research Articles: Therapeutics, Targets, and Development

Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses

¹ Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and ² Molecular and Cancer Biology Program, University of Helsinki; Departments of ³ Oncology and HUSLAB, ⁴ Urology, and ⁵ Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

Requests for reprints: Akseli Hemminki, Cancer Gene Therapy Group, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland. Phone: 358-9-1912-5464; Fax: 358-9-1912-5465. E-mail: akseli.hemminki{at}helsinki.fi

Abstract

Renal cancer is a common and deadly disease that lacks curative treatments when metastatic. Here, we have used oncolytic adenoviruses, a promising developmental approach whose safety has recently been validated in clinical trials. Although preliminary clinical efficacy data exist for selected tumor types, potency has generally been less than impressive. One important reason may be that expression of the primary receptor, coxsackie-adenovirus receptor, is often low on many or most advanced tumors, although not evaluated in detail with renal cancer. Here, we tested if fluorescence-assisted cell sorting could be used to predict efficacy of a panel of infectivity-enhanced capsid-modified marker gene expressing adenoviruses in renal cancer cell lines, clinical specimens, and subcutaneous and orthotopic murine models of peritoneally metastatic renal cell cancer. The respective selectively oncolytic adenoviruses were tested for killing of tumor cells in these models, and biodistribution after locoregional delivery was evaluated. In vivo replication was analyzed with noninvasive imaging. Ad5/3-24, Ad5-24RGD, and Ad5.pK7-24 significantly increased survival of mice compared with mock or wild-type virus and 50% of Ad5/3-24 treated mice were alive at 320 days. Because renal tumors are often highly vascularized, we investigated if results could be further improved by adding bevacizumab, a humanized antivascular endothelial growth factor antibody. The combination was well tolerated but did not improve survival, suggesting that the agents may be best used in sequence instead of together. These results set the stage for clinical testing of oncolytic adenoviruses for treatment of metastatic renal cancer currently lacking other treatment options. [Mol Cancer Ther 2007;6(10):2728–36]

Grant support: Helsinki Graduate School in Biotechnology and Molecular Biology (K. Guse), Helsinki Biomedical Graduate School (T. Ranki and M. Rajecki), and EU FP6 THERADPOX and APOTHERAPY, HUCH Research Funds (EVO), Sigrid Juselius Foundation, Academy of Finland, Emil Aaltonen Foundation, Finnish Cancer Society (A. Hemminki).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dr. Hemminki is K. Albin Johansson Research Professor of The Finnish Cancer Institute.

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 3/13/07; revised 7/11/07; accepted 8/17/07.