Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus
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Ramachandran M, Yu D, Dyczynski M, Baskaran S, Zhang L, Lulla A, Lulla V, Saul S, Nelander S, Dimberg A, Merits A, Leja-Jarblad J, Essand M
Clin. Cancer Res. 23 (6) 1519-1530 [2017-03-15; online 2016-09-16]
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 vivo neurovirulence 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 vivo therapeutic efficacy in different tumor models inversely correlated to secretion of IFNβ by respective cells upon SFV4 infection in vitro Similarly, 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.
PubMed 27637889
DOI 10.1158/1078-0432.ccr-16-0925
Crossref 10.1158/1078-0432.ccr-16-0925