Combined HSV-TK/IL-2 gene therapy in patients with recurrent glioblastoma multiforme: biological and clinical results

Abstract

Following our pilot clinical study of combined IL-2/HSV-TK gene therapy for recurrent glioblastoma multiforme (GBM), we extended the protocol to a larger population of patients and evaluated safety, feasibility, and biological activity of treatment. A total of 12 patients received intratumor injection of retroviral vector-producing cells (RVPCs), followed by intravenous ganciclovir (GCV). Treatment was well tolerated with only minor adverse events. Transduction of tumor cells was demonstrated in tumor biopsies. A marked and persistent increase of intratumor and plasma Th1 cytokine levels was demonstrated after RVPC injection. At magnetic resonance imaging evaluation, two patients had a partial response (including a patient showing disappearance of a distant noninjected tumor mass), four had a minor response, four had stable disease, and two had progressive disease. The 6- and 12-month progression-free survival rates were 47 and 14%, respectively. The 6- and 12-month overall survival rates were 58 and 25%, respectively. In conclusion, the results of our clinical protocol of gene therapy for recurrent GBM, based on combined delivery of a suicide and a cytokine gene, demonstrate that intratumor injection of RVPCs was safe, provided effective transduction of the therapeutic genes to target tumor cells, and activated a systemic cytokine cascade, with tumor responses in 50% of cases.

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

“…13 Several clinical trials support the feasibility of this approach. [14][15][16][17][18] However, HSV-tk is a viral gene and may induce an unwanted immune response against functionally desirable T cells. Activation of the system also requires a clinically useful prodrug (like ganciclovir) to be administered for cell destruction.…”

Tumor-infiltrating lymphocytes (TILs) from patients with glioma

“…Activated T cells have been able to control glioma growth using transgenic expression of IL-2, delivered by a retroviral vector. 6 Alternatively, infusion of recombinant IL-2 into patients with brain tumors (n D 5) along with allogeneic cytotoxic T cells was performed. Two of five patients succumbed to the disease and three of five showed a clinical response defined by standard imaging technologies.…”

Searching for a cure: Gene therapy for glioblastoma

“…These include combinations with IL2, IL4, histone deacetylase inhibitors, Temozolomide and with radiation therapy. [28][29][30][31][32] Whether HSV-TK75 or other HSV-TK mutants combined with ACV may perform better and with less severe side effects than GCV for the treatment of CNS tumors in combination remains to be fully determined in patients.…”