A PHASE I II STUDY OF HERPES-SIMPLEX VIRUS TYPE-1 THYMIDINE KINASE SUICIDE GENE-THERAPY FOR RECURRENT GLIOBLASTOMA/

Despite extensive surgery for glioblastoma, residual tumor cells alway s lead to relapse. Gene therapy based on retrovirus-mediated gene tran sfer of herpes simplex virus type 1 thymidine kinase (HSV-1 TK), which specifically sensitizes dividing cells to ganciclovir (GCV) toxicity, may help eradicate such cells. During glioblastoma surgery, HSV-I TK retroviral vector-producing cells (M11) were injected into the surgica l cavity margins after tumor debulking, After a 7-day transduction per iod, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by MRI-based re lapse-free survival at month 4 and by overall survival. Twelve patient s with recurrent glioblastoma mere treated without serious adverse eve nts related to M11 cell administration or GCV, Quality of life was not negatively influenced by this treatment. Overall median survival was 206 days, with 25% of the patients surviving longer than 12 months. At 4 months after treatment, 4 of 12 patients had no recurrence; their m edian overall survival was 528 days, compared with 194 days for patien ts with recurrence (p = 0.03 by the log rank test). One patient is sti ll free of detectable recurrence, steroid free and independent, 2.8 ye ars after treatment. Thus, brain injections of M11 retroviral vector-p roducing cells for glioblastoma HSV-1 TK gene therapy were well tolera ted and associated with significant therapeutic responses. These resul ts warrant further development of this therapeutic strategy in brain t umor, including recurrent glioblastoma.