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Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice

Cancer Gene Therapy volume 9, pages 432–442 (2002)Cite this article

Abstract

We have previously shown that the growth of human tumor xenografts in immunodeficient mice can be efficiently suppressed upon infection with the autonomous parvovirus H-1 or with cytokine-transducing derivatives thereof. To further evaluate the benefits of implementing parvoviruses in cancer gene therapy, we have created a new recombinant vector, MVMp/IP-10, transducing the immunoactive, antiangiogenic chemokine IP-10, and used this virus to treat syngeneic tumors grown in immunocompetent mice. Intratumoral/intraperitoneal administration of only 3×107 replication units of MVMp/IP-10 per animal strongly inhibited the progression of established H5V cell–induced vascular tumors, a highly malignant mouse model for human cavernous hemangioma and Kaposi's sarcoma. Retardation of recurrent tumor growth and suppression of life-threatening metastatic dissemination to internal organs were accompanied by a striking delay in hemangioma-associated mortality. Parental MVMp did not have a significant effect under these conditions up to the dose of 1010 infectious units/animal, but had strong antihemangiosarcoma activity when used to infect H5V cells ex vivo prior to implantation. In all cases, virus therapy was very well tolerated. Virus-induced suppression of hemangiosarcoma was dependent on host T cells and associated with intratumoral persistence of IFNγ-expressing cytotoxic lymphocytes, and led to the reduced expression of hepatic plasminogen activator inhibitor-1 (PAI-1), a metastasis-linked marker. This proof of principle study demonstrates that MVMp/IP-10 can aid the treatment of vascular tumors and that autonomous parvovirus-based vectors can be considered potent tools for cancer gene therapy purposes.

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Acknowledgements

We are grateful to JM Farber (NIH, Bethesda, MD, USA) for the mouse IP-10 cDNA clone and IP-10 primer sequences used in RT-PCR. We thank Search-LC (Heidelberg, Germany) for assistance in performing LightCycler™ QRT-PCR. We also thank the DKFZ Department of Cellular and Molecular Pathology (Director H-J Gröne) for performing histopathological examinations; and C Cziepluch and HC Morse (III) for critical reading of the manuscript. This work was supported by EU Commission Grants BIO 4 CT97-2167 and QLRT-2000-01010.

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Authors and Affiliations

  1. Applied Tumor Virology Program F0100 and INSERM U375, Deutsches Krebsforschungszentrum, Heidelberg, 69120, Germany

    Nathalia A Giese, Zachary Raykov, Luisa DeMartino, Christiane Dinsart, Jan J Cornelis & Jean Rommelaere

  2. Laboratory of Inflammation and Signal Transduction, IRF Mario Negri, Milan, 20157, Italy

    Annunciata Vecchi & Silvano Sozzani

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  1. Nathalia A Giese
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Correspondence to Nathalia A Giese.

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Giese, N., Raykov, Z., DeMartino, L. et al. Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice. Cancer Gene Ther 9, 432–442 (2002). https://doi.org/10.1038/sj.cgt.7700457

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