SFVmiRT for treatment of glioblastoma and neuroblastoma

Purpose:: Glioblastoma multiforme (GBM) and high–risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)–β–resistant Semliki Forest virus (SFV)–4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM 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 syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFN–β in inhibiting therapeutic efficacy was investigated. Results:The introduction of microRNA 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 4 of 8 mice (50%) with NXS2 and 3 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 IFN–β by respective cells upon SFV4 infection in vitro. Similarly, killing efficacy of HGCC lines inversely correlated to IFN–β response and interferon–α/β receptor (IFNAR)–1 expression. Conclusions:SFV4miRT has reduced neurovirulence, while retaining its oncolytic potential. SFV4miRT is an excellent candidate for treatment of GBMs and neuroblastomas with low IFN–β secretion.

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