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Oncolytic Herpes Simplex Virus Type-1 Therapy in a Highly Infiltrative Animal Model of Human Glioblastoma

Authors' Affiliations: ¹ Department of Biomedicine, and ² Section for Pathology, The Gade Institute, University of Bergen; Departments of ³ Oncology and Medical Physics and ⁴ Pathology, Haukeland University Hospital, Bergen, Norway; ⁵ Preclinical Development, MediGene AG, Martinsried, Germany; and ⁶ Nor-Lux Neuro-Oncology, Centre Recherché Public Santé, Luxembourg, Luxembourg

Requests for reprints: Peter C. Huszthy, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. Phone: 47-555-86063; Fax: 47-555-86360; E-mail: Peter.Huszthy{at}biomed.uib.no.

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 10⁶ plaque-forming units (penetration study) or 6.8 x 10⁶ 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.