title: In vivo safety, biodistribution and antitumor effects of uPAR retargeted oncolytic measles virus in syngeneic cancer models.
abstract: The urokinase receptor (uPAR) is a clinically relevant target for novel biological therapies. We have previously rescued oncolytic measles viruses fully retargeted against human (MV-h-uPA) or murine (MV-m-uPA) uPAR. Here, we investigated the in vivo effects of systemic administration of MV-m-uPA in immunocompetent cancer models. MV-m-uPA induced in vitro cytotoxicity and replicated in a receptor-dependent manner in murine mammary (4T1) and colon (MC-38 and CT-26) cancer cells. Intravenous administration of MV-m-uPA to 4T1 tumor-bearing mice was not associated with significant clinical or laboratory toxicity. Higher MV-N RNA copy numbers were detected in primary tumors, and viable viral particles were recovered from tumor-bearing tissues only. Non-tumor-bearing organs did not show histological signs of viral-induced toxicity. Serum anti-MV antibodies were detected at day 14 of treatment. Immunohistochemistry and immunofluorescence studies confirmed successful tumor targeting and demonstrated enhanced MV-m-uPA-induced tumor cell apoptosis in treated compared with control mice. Significant antitumor effects and prolonged survival were observed after systemic administration of MV-m-uPA in colon (CT-26) and mammary (4T1) cancer models. The above results show safety and feasibility of uPAR targeting by an oncolytic virus, and confirm significant antitumor effects in highly aggressive syngeneic immunocompetent cancer models.
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Veterinary Resources, University of Miami, Miami, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zaias
authors.affiliation: Epidemiology and Public Health Department, University of Miami, Miami, FL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Duncan
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Russell
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Merchan
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D008325:Mammary Neoplasms, Experimental / Q000628:therapy*; D008459:Measles virus / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy / Q000009:adverse effects* / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D014185:Transplantation, Isogeneic
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator