title: Oncolytic virotherapy with an armed vaccinia virus in an orthotopic model of renal carcinoma is associated with modification of the tumor microenvironment.
abstract: Oncolytic virotherapy is an emergent promising therapeutic approach for the treatment of cancer. We have constructed a vaccinia virus (WR strain) deleted for thymidine kinase (TK) and ribonucleotide reductase (RR) genes that expressed the fusion suicide geneFCU1derived from the yeast cytosine deaminase and uracil phosphoribosyltransferase genes. We evaluated this construct (VV-FCU1) in the orthotopic model of renal carcinoma (RenCa). Systemic administration of VV-FCU1 resulted in orthotopic tumor growth inhibition, despite temporary expression of viral proteins. VV-FCU1 treatment was associated with an infiltration of tumors by CD8+T lymphocytes and a decrease in the proportion of infiltrating Tregs, thus modifying the ratio of CD8+/CD4+Treg in favor of CD8+cytotoxic T cells. We demonstrated that VV-FCU1 treatment prolonged survival of animals implanted with RenCa cells in kidney. Depletion of CD8+T cells abolished the therapeutic effect of VV-FCU1 while depletion of CD4+T cells enhanced its protective activity. Administration of the prodrug 5-fluorocytosine (5-FC) resulted in a sustained control of tumor growth but did not extend survival. This study shows the importance of CD4+and CD8+T cells in vaccinia virus-mediated oncolytic virotherapy and suggests that this approach may be evaluated for the treatment of human renal cell carcinoma.
authors.affiliation: Transgene S.A., 400 boulevard Gonthier d'Andernach, Parc d'innovation, CS80166, Illkirch-Graffenstaden Cedex, France and Institut Gustave Roussy, Unité INSERM 1015 114 rue Edouard-Vaillant , 94805 Villejuif Cedex, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fend
authors.affiliation: Transgene S.A., 400 boulevard Gonthier d'Andernach, Parc d'innovation, CS80166, Illkirch-Graffenstaden Cedex, France and Institut Gustave Roussy, Unité INSERM 1015 114 rue Edouard-Vaillant , 94805 Villejuif Cedex, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Remy-Ziller
authors.affiliation: Transgene S.A., 400 boulevard Gonthier d'Andernach, Parc d'innovation, CS80166, Illkirch-Graffenstaden Cedex, France and Institut Gustave Roussy, Unité INSERM 1015 114 rue Edouard-Vaillant , 94805 Villejuif Cedex, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Foloppe
authors.affiliation: Transgene S.A., 400 boulevard Gonthier d'Andernach, Parc d'innovation, CS80166, Illkirch-Graffenstaden Cedex, France and Institut Gustave Roussy, Unité INSERM 1015 114 rue Edouard-Vaillant , 94805 Villejuif Cedex, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Kempf
authors.affiliation: Transgene S.A., 400 boulevard Gonthier d'Andernach, Parc d'innovation, CS80166, Illkirch-Graffenstaden Cedex, France and Institut Gustave Roussy, Unité INSERM 1015 114 rue Edouard-Vaillant , 94805 Villejuif Cedex, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cochin
authors.affiliation: Transgene S.A., 400 boulevard Gonthier d'Andernach, Parc d'innovation, CS80166, Illkirch-Graffenstaden Cedex, France and Institut Gustave Roussy, Unité INSERM 1015 114 rue Edouard-Vaillant , 94805 Villejuif Cedex, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Barraud
authors.affiliation: Novartis Institutes for Biomedical Research, Analytical Sciences and Imaging , WSJ386, Basel, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Accart
authors.affiliation: Transgene S.A., 400 boulevard Gonthier d'Andernach, Parc d'innovation, CS80166, Illkirch-Graffenstaden Cedex, France and Institut Gustave Roussy, Unité INSERM 1015 114 rue Edouard-Vaillant , 94805 Villejuif Cedex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Erbs
authors.affiliation: Laboratoire de Conception et Application de Molécules Bioactives, Equipe de Biovectorologie, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie , 74 Route du Rhin- BP60024 , Illkirch-Graffenstaden Cedex, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel
authors.affiliation: Transgene S.A., 400 boulevard Gonthier d'Andernach, Parc d'innovation, CS80166, Illkirch-Graffenstaden Cedex, France and Institut Gustave Roussy, Unité INSERM 1015 114 rue Edouard-Vaillant , 94805 Villejuif Cedex, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Préville
keywords: Oncolytic virotherapy; regulatory T cells; renal carcinoma; suicide gene therapy; tumor microenvironment; vaccinia virus