title: Oncolytic herpes simplex virus type-1 therapy in a highly infiltrative animal model of human glioblastoma.
abstract: We have examined the spread and antitumor efficacy of an oncolytic herpes simplex virus-1-based vector (G207) in glioblastoma biopsy spheroids in vitro and in vivo after local delivery to corresponding intracranial xenografts. Spheroids from three patients were infected with increasing doses of G207 and transgene expression was quantified. Other infected spheroids were followed for 10 days to assess cytotoxic effects. For the in vivo study, spheroids were grafted intracerebrally into Rowett nude rats. The resulting highly infiltrative xenografts were injected with 3.4 x 10(6) plaque-forming units (penetration study) or 6.8 x 10(6) plaque-forming units (therapeutic study) of G207 using microprocessor-controlled stereotaxic delivery. Vector spread was tracked by histochemical staining. In the therapeutic study, tumor volumes were monitored weekly by magnetic resonance imaging, and survival data were collected. In vitro, lacZ expression was seen at the spheroid surfaces 24 h postinfection, whereas the spheroid cores were transgene positive after 96 h. Cytotoxic susceptibility varied between the patients, showing a 36% to 95% lysis 10 days postinfection. Local delivery of G207 into intracranial xenografts resulted in extensive vector spread throughout the lesions. In the therapeutic study, G207 application reduced tumor volumes compared with controls, but did not significantly improve survival of the animals. Histologic analysis revealed infection of host structures such as the ventricular and choroid plexus ependyma. In conclusion, G207 replicates in patient-derived glioblastoma multiforme xenografts and tumor volumes are reduced after intratumoral delivery; however, the survival data suggest that the therapeutic effect could be improved by repeated vector application or through combination with other treatment modalities.
authors.affiliation: Department of Biomedicine, The Gade Institute, University of Bergen, Bergen, Norway. Peter.Huszthy@biomed.uib.no
authors.forename: Peter C
authors.initials: PC
authors.lastname: Huszthy
authors.forename: Dorota
authors.initials: D
authors.lastname: Goplen
authors.forename: Frits
authors.initials: F
authors.lastname: Thorsen
authors.forename: Heike
authors.initials: H
authors.lastname: Immervoll
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Anja
authors.initials: A
authors.lastname: Gutermann
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
mesh_terms: D000818:Animals; D002470:Cell Survival; D003588:Cytopathogenic Effect, Viral; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000008:administration & dosage; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D007763:Lac Operon; D008279:Magnetic Resonance Imaging; D050130:Oncolytic Virotherapy; D051381:Rats; D011923:Rats, Nude; D018874:Spheroids, Cellular; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000821:virology; D014779:Virus Replication