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

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 3Â10 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.

Activation of a glioma-specific immune response by oncolytic parvovirus Minute Virus of Mice infection

“…This prompted us to choose, for the present proof-of-principle study, the prototype strain of Minute Virus of Mice (MVMp), another oncolytic PV, which is closely related to H-1PV but has a different host range, enabling its propagation in mouse tumors. 9 We initially hypothesized that virus-induced volatility (including lysis) of tumor cells may contribute to activate antigen-presenting cells (APCs), thereby stimulating the induction of an adaptive tumor-specific immune response. This study aims to analyze this hypothesis using MVMp and the established mouse GL261 glioma model.…”

MCP‐3 (CCL7) delivered by parvovirus MVMp reduces tumorigenicity of mouse melanoma cells through activation of T lymphocytes and NK cells

“…18,[22][23][24][25] As a consequence, the capsid-replacement vectors are defective as they fail to produce progeny recombinant virus upon their infection, but are capable to produce transiently high levels of transgene products. 21,26 The fibrotropic variant of the mouse parvovirus minute virus of mice (MVMp) does not seem to induce strong cytotoxic T cell responses (unpublished) or severe inflammatory reactions 20 against incoming virus components, an interesting feature for their use as anticancer agents. These properties and the promising antitumor effects of recombinant parvoviruses, transducing IL-2 and interferon g-inducible protein 10 (IP-10/CXCL10) in various tumor models, [19][20][21] underline the possible utility of these novel therapeutics.…”

“…21,26 The fibrotropic variant of the mouse parvovirus minute virus of mice (MVMp) does not seem to induce strong cytotoxic T cell responses (unpublished) or severe inflammatory reactions 20 against incoming virus components, an interesting feature for their use as anticancer agents. These properties and the promising antitumor effects of recombinant parvoviruses, transducing IL-2 and interferon g-inducible protein 10 (IP-10/CXCL10) in various tumor models, [19][20][21] underline the possible utility of these novel therapeutics. Furthermore, we have previously shown that human cervical tumor cells that had been infected with a parvoviral vector expressing human MCP-3 grew significantly slower in nude mice than noninfected tumors.…”

“…14 Because of these properties, both natural [15][16][17] and recombinant parvoviruses (vectors) [18][19][20][21][22] have attracted interest as tools to treat cancer. The recombinant parvoviruses that were developed so far as anticancer agents are so-called capsid-replacement vectors, i.e.…”

Potential of tumour cells for delivering oncolytic viruses

“…41 On the other hand, the endotheliotropism of certain parvoviruses raises the possibility of using activated endothelial cells to deliver these agents. 42 Whether other precursor cells might be conditioned so as to transfer OVs to specific tissues remains to be explored.…”