Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice.
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 x 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 gamma-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.
Giese
Nathalia A
NA
Applied Tumor Virology Program F0100 and INSERM U375, Deutsches Krebsforschungszentrum, Heidelberg 69120, Germany. n.giese@dkfz-heidelberg.de
Raykov
Zachary
Z
DeMartino
Luisa
L
Vecchi
Annunciata
A
Sozzani
Silvano
S
Dinsart
Christiane
C
Cornelis
Jan J
JJ
Rommelaere
Jean
J
D000818:Animals; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics*; D004396:Coloring Agents / Q000494:pharmacology; D004727:Endothelium / Q000166:cytology; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006394:Hemangiosarcoma / Q000628:therapy*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008915:Minute Virus of Mice / Q000235:genetics*; D009362:Neoplasm Metastasis; D017992:Parvovirus / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D019076:Transgenes; D014407:Tumor Cells, Cultured
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue