Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice Nathalia A Giese, 1 Zachary Raykov, 1 Luisa DeMartino, 1 Annunciata Vecchi, 2 Silvano Sozzani, 2 Christiane Dinsart, 1 Jan J Cornelis, 1 and Jean Rommelaere 1 1 Applied Tumor Virology Program F0100 and INSERM U375, Deutsches Krebsforschungszentrum, Heidelberg 69120, Germany; and 2 Laboratory of Inflammation and Signal Transduction, IRF Mario Negri, Milan 20157, Italy. 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10 7 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 10 10 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 IFN - 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. Cancer Gene Therapy (2002) 9, 432 – 442 DOI: 10.1038 / sj / cgt / 7700457 Keywords: hemangiosarcoma; metastasis; parvovirus MVMp; IP - 10; IFN; PAI-1 V irus - based anticancer therapies involve the use of viruses either as replicating oncolytic agents, or as recombinant vectors for gene transfer. 1 The autonomous parvoviruses MVMp and H-1 belong to a group of small ( 5 kb ) nonintegrating single - stranded DNA viruses. Their oncotropic and oncotoxic properties make them good candidates for both types of applications. 2 Malignant transformation of a number of rodent and human cells correlates with their increased capacity to amplify and / or express parvoviral DNA, and with hypersensitivity to parvovirus - induced killing. 3 These features contribute to the intrinsic oncosuppressive capacity of these viruses, but they are often insufficient to promote full inhibition of oncogenesis. 4,5 Therefore, we are developing strategies to reinforce the antineoplastic activity of parvoviruses through incorporation of therapeutic transgenes. 6 Although the MVMp - and H - 1 – based vectors produced so far are unable to generate progeny virions, they retain their genuine parvoviral promoters and replication origins, and encode the pivotal nonstructural protein, NS1. 7 These features allow amplification of the viral genome, efficient expression of inserted transgenes, and limited oncotoxicity. 7,8 Parvovirus vectors are expected to be relatively safe, being poorly expressed in quiescent cells and most nontransformed cells. 3,8 Furthermore, the MVMp and H-1 viruses are weakly immunogenic and rarely pathogenic to adult animals: the infections they cause can be abortive or persistent, but they are usually clinically nonapparent. 9,10 We have recently demonstrated that wild-type H-1 virus can reduce the tumorigenicity of HeLa xenografts in immunodeficient mice, and that recombinant derivatives transducing various cytokines (IL-2, MCP-3) are more efficient antineoplastic agents than the parental virus. 11,12 Our current focus is on assessing the antitumor activity of autonomous parvovirus vectors in immunocompetent hosts, and on identifying target malignancies for parvovirus-based anticancer therapy. In the present work, MVMp, known to target transformed cells of both human and murine origin, and recombinant MVMp derivatives were tested for their ability to protect mice against a very aggressive mouse hemangiosarcoma. Received February 11, 2002. Address correspondence and reprint requests to: Dr Nathalia A Giese, Applied Tumor Virology Program F0100 and INSERM U375, Deutsches Krebsforschungszentrum, Heidelberg 69120, Germany. E - mail: n.giese@dkfz - heidelberg.de Cancer Gene Therapy (2002) 9, 432 – 442 D 2002 Nature Publishing Group All rights reserved 0929-1903 / 02 $25.00 www.nature.com/ cgt