title: Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases.
abstract: Fully retargeted oncolytic herpes simplex viruses (o-HSVs) gain cancer-specificity from redirection of tropism to cancer-specific receptors, and are non-attenuated. To overcome the hurdles of systemic delivery, and enable oncolytic viruses (o-viruses) to reach metastatic sites, carrier cells are being exploited. Mesenchymal stromal cells (MSCs) were never tested as carriers of retargeted o-viruses, given their scarse-null expression of the cancer-specific receptors. We report that MSCs from different sources can be forcedly infected with a HER2-retargeted oncolytic HSV. Progeny virus spread from MSCs to cancer cells in vitro and in vivo. We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v. injection of infected MSCs. As expected, the highest concentration of carrier-cells and of viral genomes was in the lungs. Viral genomes persisted throughout the body for at least two days. The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment significantly inhibited also breast cancer metastases to the brain in NSG mice, and reduced by more than one-half the metastatic burden in the brain.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Leoni
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gatta
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Palladini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Giordano
authors.initials: G
authors.lastname: Nicoletti
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Ranieri
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Dall'Ora
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Grosso
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Alviano
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonsi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nanni
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Lollini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Campadelli-Fiume
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000821:virology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses; D010051:Ovarian Neoplasms / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D018139:Simplexvirus; D023041:Xenograft Model Antitumor Assays
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: mesenchymal stem cells; metastases; oncolytic herpes simplex virus; systemic delivery; viral retargeting