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Oncolytic adenovirus based on serotype 3

Cancer Gene Therapy volume 18, pages 288–296 (2011)Cite this article

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Abstract

Oncolytic adenoviruses have been safe in clinical trials but the efficacy has been mostly limited. All published trials have been performed with serotype 5 based viruses. The expression level of the Ad5 receptor CAR may be variable in advanced tumors. In contrast, the Ad3 receptor remains unclear, but is known to be abundantly expressed in most tumors. Therefore, we hypothesized that a fully serotype 3 oncolytic adenovirus might be useful for treating cancer. Patients exposed to adenoviruses develop high titers of serotype-specific neutralizing antibodies, which might compromise re-administration. Thus, having different serotype oncolytic viruses available might facilitate repeated dosing in humans. Ad3-hTERT-E1A is a fully serotype 3 oncolytic adenovirus controlled by the promoter of the catalytic domain of human telomerase. It was effective in vitro on cell lines representing seven major cancer types, although low toxicity was seen in non-malignant cells. In vivo, the virus had anti-tumor efficacy in three different animal models. Although in vitro oncolysis mediated by Ad3-hTERT-E1A and wild-type Ad3 occurred more slowly than with Ad5 or Ad5/3 (Ad3 fiber knob in Ad5) based viruses, in vivo the virus was at least as potent as controls. Anti-tumor efficacy was retained in presence of neutralizing anti-Ad5 antibodies whereas Ad5 based controls were blocked. In summary, we report generation of a non-Ad5 based oncolytic adenovirus, which might be useful for testing in cancer patients, especially in the context of high anti-Ad5 neutralizing antibodies.

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Acknowledgements

We thank Eerika Karli, Aila Karioja-Kallio, Kikka Holm and Päivi Hannuksela for expert assistance. This study was supported by National Graduate School of Clinical Investigation, the European Research Council, EU FP6 APOTHERAPY and THERADPOX, HUCH Research Funds (EVO), Finnish Cancer Society, Sigrid Juselius Foundation, Academy of Finland, Biocentrum Helsinki and University of Helsinki. Silvio Hemmi is supported by the Cancer Society of the Kanton Zurich, Switzerland. Akseli Hemminki is K. Albin Johansson Research Professor of the Foundation for the Finnish Cancer Institute.

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Authors and Affiliations

  1. Cancer Gene Therapy Group, Molecular Cancer Biology Program and Haartman Institute and Transplantation Laboratory and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland

    O Hemminki, G Bauerschmitz, S Lavilla-Alonso, I Diaconu, K Guse, A Koski, A Kanerva, V Cerullo, S Pesonen & A Hemminki

  2. HUSLAB, Helsinki University Central Hospital, Helsinki, Finland

    O Hemminki, G Bauerschmitz, S Lavilla-Alonso, I Diaconu, K Guse, A Koski, M Lappalainen, V Cerullo, S Pesonen & A Hemminki

  3. Department of OB/GYN, Duesseldorf University Medical Center, Duesseldorf, Germany

    G Bauerschmitz

  4. Institute of Molecular Biology, University of Zurich, Zurich, Switzerland

    S Hemmi

  5. Biostatistics and Bioinformatics Unit, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    R A Desmond

  6. Department of OB/GYN, Helsinki University Central Hospital, Helsinki, Finland

    A Kanerva

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Correspondence to A Hemminki.

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Work for this publication has been done in Helsinki Biomedicum, Helsinki, Finland.

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Hemminki, O., Bauerschmitz, G., Hemmi, S. et al. Oncolytic adenovirus based on serotype 3. Cancer Gene Ther 18, 288–296 (2011). https://doi.org/10.1038/cgt.2010.79

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