title: Pediatric and Adult High-Grade Glioma Stem Cell Culture Models Are Permissive to Lytic Infection with Parvovirus H-1.
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.
authors.affiliation: Research Program Infection, Inflammation and Cancer, Division of Tumor Virology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. rafael.josupeit@googlemail.com.
authors.forename: Rafael
authors.initials: R
authors.lastname: Josupeit
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. SeBender@gmx.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bender
authors.affiliation: Research Program Infection, Inflammation and Cancer, Division of Tumor Virology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. sonja.kern@uni-wuerzburg.de.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kern
authors.affiliation: Research Program Infection, Inflammation and Cancer, Division of Tumor Virology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. b.leuchs@dkfz-heidelberg.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Leuchs
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. t.hielscher@dkfz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. h.mende@med.uni-heidelberg.de.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: Research Program Infection, Inflammation and Cancer, Division of Tumor Virology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. joteres@arcor.de.
authors.forename: Jörg R
authors.initials: JR
authors.lastname: Schlehofer
authors.affiliation: Research Program Infection, Inflammation and Cancer, Division of Tumor Virology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. c.dinsart@dkfz-heidelberg.de.
authors.forename: Christiane
authors.initials: C
authors.lastname: Dinsart
authors.affiliation: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. o.witt@dkfz.de.|Department of Pediatric Hematology, Oncology and Immunology, Center for Pediatric and Adolescent Medicine, University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. o.witt@dkfz.de.
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.affiliation: Research Program Infection, Inflammation and Cancer, Division of Tumor Virology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. j.rommelaere@dkfz-heidelberg.de.
authors.forename: Jean
authors.initials: J
authors.lastname: Rommelaere
authors.affiliation: Research Program Infection, Inflammation and Cancer, Division of Tumor Virology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. jeannine.lacroix@dkfz-heidelberg.de.|Department of Pediatric Hematology, Oncology and Immunology, Center for Pediatric and Adolescent Medicine, University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. jeannine.lacroix@dkfz-heidelberg.de.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Lacroix
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005910:Glioma / Q000628:therapy; D052661:H-1 parvovirus / Q000254:growth & development*; D064593:Heterografts; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008962:Models, Theoretical; D009457:Neuroglia / Q000502:physiology* / Q000821:virology*; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000254:growth & development*; D013234:Stem Cells / Q000502:physiology* / Q000821:virology*
keywords: DIPG; H-1PV; glioma stem-like cells; high-grade glioma; oncolytic virus; parvovirus H-1; pediatric glioblastoma; tumor initiating cells