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Antitumor efficacy of AAV-mediated systemic delivery of interferon-β

Cancer Gene Therapy volume 13, pages 99–106 (2006)Cite this article

Abstract

Type I interferons (α/β) have significant antitumor activity although their short half-life and systemic side effects have limited their clinical utility. An alternative dosing schedule of continuous, low-level delivery, as is achieved by gene therapy, rather than intermittent, high concentration pulsed-dosing, might avoid the toxicity of interferon while maintaining its antitumor efficacy. We have tested a gene therapy approach in murine tumor models to treat malignancies that have shown responsiveness to interferon in clinical trials. The tumor cell lines used were moderately sensitive to the direct effects of human interferon-β (hIFN-β) in vitro. For in vivo testing, systemic delivery of hIFN-β was generated following liver-targeted delivery of adeno-associated virus (AAV) vector carrying the hIFN-β transgene. This prevented engraftment of subcutaneous human gliomas, and orthotopic, localized (intrarenal) and disseminated (primarily pulmonary) human renal cell carcinomas; and caused regression of established tumors at these sites. In a syngeneic, immunocompetent model of melanoma, AAV IFN-β treatment limited subcutaneous tumor growth and prevented disseminated disease. A significant decrease in mean intratumoral vessel density was demonstrated in hIFN-β-treated tumors, suggesting that in addition to a direct tumoricidal effect, the antitumor efficacy of AAV IFN-β in this study was due to its ability to inhibit angiogenesis.

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Acknowledgements

This work was supported by The Alliance for Cancer Gene Therapy, as well as grants from the Assisi Foundation of Memphis 94-000, Grant #IRG-87-008-09 from the American Cancer Society, Cancer Center Support CORE Grant, P30 CA 21765 and American Lebanese Syrian Associated Charities (ALSAC). We thank Dorothy Bush for her assistance with immunohistochemistry and Stacey Glass for her assistance with ultrasonography.

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Authors and Affiliations

  1. Department of Surgery, St Jude Children's Research Hospital, TN, USA

    C J Streck, P V Dickson, C Y C Ng, J Zhou, M M Hall & A M Davidoff

  2. Department of Surgery, University of Tennessee College of Medicine, Memphis, TN, USA

    C J Streck, P V Dickson & A M Davidoff

  3. Department Hematology/Oncology, St Jude Children's Research Hospital, TN, USA

    J T Gray

  4. Department of Hematology/Oncology, University College London, London, UK

    A C Nathwani

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  1. C J Streck
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Correspondence to A M Davidoff.

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Streck, C., Dickson, P., Ng, C. et al. Antitumor efficacy of AAV-mediated systemic delivery of interferon-β. Cancer Gene Ther 13, 99–106 (2006). https://doi.org/10.1038/sj.cgt.7700878

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