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.