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A human adenoviral vector with a chimeric fiber from canine adenovirus type 1 results in novel expanded tropism for cancer gene therapy

Gene Therapy volume 12, pages 1696–1706 (2005)Cite this article

Abstract

The development of novel therapeutic strategies is imperative for the treatment of advanced cancers like ovarian cancer and glioma, which are resistant to most traditional treatment modalities. In this regard, adenoviral (Ad) cancer gene therapy is a promising approach. However, the gene delivery efficiency of human serotype 5 recombinant adenoviruses (Ad5) in cancer gene therapy clinical trials to date has been limited, mainly due to the paucity of the primary Ad5 receptor, the coxsackie and adenovirus receptor (CAR), on human cancer cells. To circumvent CAR deficiency, Ad5 vectors have been retargeted by creating chimeric fibers possessing the knob domains of alternate human Ad serotypes. Recently, more radical modifications based on ‘xenotype’ knob switching with non-human adenovirus have been exploited. Herein, we present the characterization of a novel vector derived from a recombinant Ad5 vector containing the canine adenovirus serotype 1 (CAV-1) knob (Ad5Luc1-CK1), the tropism of which has not been previously described. We compared the function of this vector with our other chimeric viruses displaying the CAV-2 knob (Ad5Luc1-CK2) and Ad3 knob (Ad5/3Luc1). Our data demonstrate that the CAV-1 knob can alter Ad5 tropism through the use of a CAR-independent entry pathway distinct from that of both Ad5Luc1-CK2 and Ad5/3-Luc1. In fact, the gene transfer efficiency of this novel vector in ovarian cancer cell lines, and more importantly in patient ovarian cancer primary tissue slice samples, was superior relative to all other vectors applied in this study. Thus, CAV-1 knob xenotype gene transfer represents a viable means to achieve enhanced transduction of low-CAR tumors.

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Acknowledgements

This work was supported by the following grants: Grant of the Deutsche Forschungsgemeinschaft Sto 647/1-1 (to MA Stoff-Khalili); Department of Defense W81XWH-05-1-0035, NIH Grant R01CA083821, R01CA94084 (to DT Curiel); R01CA93796 (to GP Siegal). We thank Lucretia Sumerel for invaluable technical assistance. DNA vectors pSHAFT, pNEB.PK.3.6, and pVK700 were generous gifts from Dr Victor Krasnykh.

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Authors and Affiliations

  1. Departments of Medicine, Division of Human Gene Therapy, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA

    M A Stoff-Khalili, A A Rivera, J N Glasgow, L P Le, A Stoff, M Everts, Y Tsuruta, Y Kawakami, L Pereboeva & D T Curiel

  2. Department of Obstetrics and Gynecology, University of Duesseldorf, Medical Center, Duesseldorf, Germany

    M A Stoff-Khalili, G J Bauerschmitz & P Dall

  3. Department of Plastic and Reconstructive Surgery, Dreifaltigkeits-Hospital, Wesseling, Germany

    A Stoff

  4. Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, USA

    J M Mathis

  5. Department of Pathology, Cellular Biology and Surgery and the Gene Therapy Center, UAB, Birmingham, AL, USA

    G P Seigal

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  1. M A Stoff-Khalili
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  2. A A Rivera
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Stoff-Khalili, M., Rivera, A., Glasgow, J. et al. A human adenoviral vector with a chimeric fiber from canine adenovirus type 1 results in novel expanded tropism for cancer gene therapy. Gene Ther 12, 1696–1706 (2005). https://doi.org/10.1038/sj.gt.3302588

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  • DOI: https://doi.org/10.1038/sj.gt.3302588

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