Effective treatment of experimental glioblastoma by HSV vector-mediated TNF alpha and HSV-tk gene transfer in combination with radiosurgery and ganciclovir administration

Experiments were carried out in a nude mouse model of human glioblastoma to determine whether gamma-knife radiosurgery combined with herpes simplex vi rus thymidine kinase (tk) suicide gene therapy and tumor necrosis factor al pha (TNF alpha) gene transfer provided an improved multimodality treatment of this disease. Animals were inoculated intracerebrally with 2 X 10(5) U-8 7MG human glioblastoma cells to establish brain tumors. At 3 days postinocu lation, the tumor region was injected with 2 x 10(6) infectious particles o f highly defective herpes simplex viral vectors expressing the viral tk gen e with the kinetics of a viral immediate early gene either alone (T.1) or t ogether with TNF alpha (TH:TNF). Subgroups of animals were given dairy intr aperitoneal injections of ganciclovir (GCV) for 10 days and/or subjected to gamma-knife radiosurgery on the fifth day post tumor-cell implantation. Co mparisons of animal survival showed that the TH:TNF vector in combination w ith radiosurgery and GCV administration provided the most effective therapy ; eight of nine animals survived for 75 days compared to four of eight usin g the next best protocol. These findings suggest that gene therapy in combi nation with more conventional therapeutic methods may provide an improved s trategy for extending the life expectancy of patients afflicted with this u ltimately fatal disease.