Abstract

Combining virus-induced cytotoxic and immunotherapeutic effects, oncolytic virotherapy represents a promising therapeutic approach for high-grade glioma (HGG). A clinical trial has recently provided evidence for the clinical safety of the oncolytic parvovirus H-1 (H-1PV) in adult glioblastoma relapse patients. The present study assesses the efficacy of H-1PV in eliminating HGG initiating cells. H-1PV was able to enter and to transduce all HGG neurosphere culture models (n = 6), including cultures derived from adult glioblastoma, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Cytotoxic effects induced by the virus have been observed in all HGG neurospheres at half maximal inhibitory concentration (IC50) doses of input virus between 1 and 10 plaque forming units per cell. H-1PV infection at this dose range was able to prevent tumorigenicity of NCH421k glioblastoma multiforme (GBM) “stem-like” cells in NOD/SCID mice. Interestingly NCH421R, an isogenic subclone with equal capacity of xenograft formation, but resistant to H-1PV infection could be isolated from the parental NCH421k culture. To reveal changes in gene expression associated with H-1PV resistance we performed a comparative gene expression analysis in these subclones. Several dysregulated genes encoding receptor proteins, endocytosis factors or regulators innate antiviral responses were identified and represent intriguing candidates for to further study molecular mechanisms of H-1PV resistance.

Highlights

  • High-grade glioma in children, adolescents, and adult patients comprises a spectrum of diseases, for which current treatment protocols only can offer little hope for cure

  • In children with high-grade glioma (HGG) current clinical trials evaluate the therapeutic benefit of temozolomide treatment and the role of prognostic factors defined in adult glioblastoma multiforme (GBM) such as 1p19q status, isocitrate dehydrogenase (IDH) mutation status, and O6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation status [6]

  • The present study demonstrates for the first time, that H-1 parvovirus (H-1PV) is able to induce lytic infection in HGG stem-like cells derived from adult and pediatric high-grade glioma, and to suppress tumorigenicity of glioma stem-like cell in SCID mice

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Summary

Introduction

High-grade glioma in children, adolescents, and adult patients comprises a spectrum of diseases, for which current treatment protocols only can offer little hope for cure. Resectability of the tumor has remained a main determinant of the outcome of the disease in pediatric high-grade glioma (HGG) patients for more than three decades [3,4]. Since temozolomide had gained approval in 2005, no further treatment option has significantly improved survival of adult GBM patients. In children with HGG current clinical trials evaluate the therapeutic benefit of temozolomide treatment and the role of prognostic factors defined in adult GBM such as 1p19q status, isocitrate dehydrogenase (IDH) mutation status, and O6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation status [6]

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