A Phase I/II Study of Herpes Simplex Virus Type 1 Thymidine Kinase “Suicide” Gene Therapy for Recurrent Glioblastoma

Abstract

Despite extensive surgery for glioblastoma, residual tumor cells always lead to relapse. Gene therapy based on retrovirus-mediated gene transfer 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-1 TK retroviral vector-producing cells (M11) were injected into the surgical cavity margins after tumor debulking. After a 7-day transduction period, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by MRI-based relapse-free survival at month 4 and by overall survival. Twelve patients with recurrent glioblastoma were treated without serious adverse events 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 median overall survival was 528 days, compared with 194 days for patients with recurrence (p=0.03 by the log rank test). One patient is still free of detectable recurrence, steroid free and independent, 2.8 years after treatment. Thus, brain injections of M11 retroviral vector-producing cells for glioblastoma HSV-1 TK gene therapy were well tolerated and associated with significant therapeutic responses. These results warrant further development of this therapeutic strategy in brain tumor, including recurrent glioblastoma.

Extent of tumor—brain interface: a new tool to predict evolution of malignant gliomas

“…12 There was no significant relationship between STV or TV and existence of a response (p = 0.08). The median duration of survival was 546 days for responding and 175 days for nonresponding patients.…”

“…4,8 In agreement with these observations, in all patients in this clinical trial the relapses occurred inside or near the surgical cavity. 12 In fact, these cells probably represent the aggressive portion of the tumor in terms of biological activity. Their malignant behavior can be related to a higher mitotic activity, but also to an increased ability to migrate from the tumor to the normal brain.…”

Dicistronic MLV-retroviral vectors transduce neural precursors in vivoand co-express two genes in their differentiated neuronal progeny

“…Human placental alkaline phosphatase (PLAP) and neomycin phosphotransferase (Neo) used in this study as reporter genes can be replaced by other genes of interest to make these dicistronic vectors a novel tool to trace lineages and assess the function of specific genes in rodent CNS in vivo . Vectors might also be ideally suited to targeting suicide genes to proliferating cells, such as tumor cells, that spread and infiltrate via the CSF [61,62]. …”

The art of gene therapy for glioma: a review of the challenging road to the bedside

“…Retro-mediated and adenoviral-mediated herpes simplex type 1 thymidine kinase (HSV-tk) gene therapies are the most commonly studied in clinical trials. Retrovirus: Prados et al, 9 Rainov, 10 Shand et al, 11 Palu et al, 12 Klatzmann et al, 13 Izquierdo et al 14 and Ram et al 15 Adenovirus: Trask et al, 16 Sandmair et al, 17 Smitt et al, 18 Germano et al, 19 Immonen et al 20 been observed when only w10% of total tumour cells in the disease burden are transduced with HSV-tk. 17 37 In the clinic, successful delivery of the HSV-tk system into the tumour cavity has been achieved by replication-defective retrovirus (RV), adenovirus (Adv), cell carrier and reovirus packing cells.…”