title: Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus.
abstract: Background:Glioblastoma multiforme and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic approach for these malignancies. Here we evaluate the oncolytic capacity of the neurovirulent and partly IFNβ-resistant Semliki Forest virus (SFV)-4 in glioblastoma multiformes and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal central nervous system (CNS) cells through insertion of microRNA target sequences for miR124, miR125, miR134.Methods:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and glioblastoma multiforme cell lines and in patient-derived human glioblastoma cell cultures (HGCC).In vivoneurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT-2A, GL261) and a syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFNβ in inhibiting therapeutic efficacy was investigated.Results:The introduction of miRNA target sequences reduced neurovirulence of SFV4 in terms of attenuated replication in mouse CNS cells and ability to cause encephalitis when administered intravenously. A single intravenous injection of SFV4miRT prolonged survival and cured four of eight mice (50%) with NXS2 and three of 11 mice (27%) with CT-2A, but not for GL261 tumor-bearing mice.In vivotherapeutic efficacy in different tumor models inversely correlated to secretion of IFNβ by respective cells upon SFV4 infectionin vitroSimilarly, killing efficacy of HGCC lines inversely correlated to IFNβ response and interferon-α/β receptor-1 expression.Conclusions:SFV4miRT has reduced neurovirulence, while retaining its oncolytic capacity. SFV4miRT is an excellent candidate for treatment of glioblastoma multiforme and neuroblastoma with low IFN-β secretion.Clin Cancer Res; 23(6); 1519-30. ©2016 AACR.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Ramachandran
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Matheus
authors.initials: M
authors.lastname: Dyczynski
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Sathishkumar
authors.initials: S
authors.lastname: Baskaran
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Aleksei
authors.initials: A
authors.lastname: Lulla
authors.affiliation: Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Valeria
authors.initials: V
authors.lastname: Lulla
authors.affiliation: Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Sirle
authors.initials: S
authors.lastname: Saul
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
authors.affiliation: Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Merits
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Justyna
authors.initials: J
authors.lastname: Leja-Jarblad
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. magnus.essand@igp.uu.se.
authors.forename: Magnus
authors.initials: M
authors.lastname: Essand
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000821:virology; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000235:genetics / Q000628:therapy* / Q000821:virology; D006801:Humans; D016899:Interferon-beta / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000627:therapeutic use; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy* / Q000821:virology; D009447:Neuroblastoma / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000009:adverse effects; D050504:Oncolytic Viruses / Q000235:genetics*; D012672:Semliki forest virus / Q000235:genetics
chemical_list: D035683:MicroRNAs; D016899:Interferon-beta