Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration

• Published in: Journal of neurosurgery Vol. 92; no. 2; pp. 249 - 254
• Main Authors: PACKER, R. J, RAFFEL, C, KAPCALA, L. P, VILLABLANCA, J. G, TONN, J.-C, BURDACH, S. E, BURGER, K, LAFOND, D, MCCOMB, J. G, COGEN, P. H, VEZINA, G
• Format: Journal Article
• Language: English
• Published: Park Ridge, IL American Association of Neurological Surgeons 01-02-2000
• Subjects: Adolescent; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Biological and medical sciences; Brain - pathology; Cell Death - genetics; Child; Combined Modality Therapy; Disease-Free Survival; Ependymoma - genetics; Ependymoma - pathology; Ependymoma - therapy; Female; Ganciclovir - administration & dosage; Ganciclovir - adverse effects; Genetic Therapy - methods; Genetic Vectors - genetics; Glioma - genetics; Glioma - pathology; Glioma - therapy; Humans; Infusions, Intravenous; Injections, Intralesional; Magnetic Resonance Imaging; Male; Medical sciences; Mice; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Neoplasm Recurrence, Local - therapy; Neuroectodermal Tumors, Primitive - genetics; Neuroectodermal Tumors, Primitive - pathology; Neuroectodermal Tumors, Primitive - therapy; Neurology; Quality of Life; Simplexvirus - genetics; Supratentorial Neoplasms - genetics; Supratentorial Neoplasms - pathology; Supratentorial Neoplasms - therapy; Thymidine Kinase - genetics; Tumors of the nervous system. Phacomatoses; Human; Intracranial; Nervous system diseases; Acyclic nucleoside; Purine nucleoside; Retroviridae; Recurrent; Malignant tumor; Cerebral disorder; Virus; Chemotherapy; Ganciclovir; Central nervous system disease; Phase I trial; Combined treatment; Gene therapy; Child
• ISSN: 0022-3085; 1933-0693
• DOI: 10.3171/jns.2000.92.2.0249

The outcome for children with recurrent malignant brain tumors is poor. The majority of patients die of progressive disease within months of relapse, and other therapeutic options are needed. The goal of this Phase I study was to evaluate the safety of in vivo suicide gene therapy in 12 children with recurrent, malignant, supratentorial brain tumors.
After optimal repeated tumor resection, multiple injections of murine vector-producing cells shedding murine replication-defective retroviral vectors coding the herpes simplex virus thymidine kinase type 1 (HSV-Tk1) gene were made into the rim of the resection cavity. Fourteen days after the vector-producing cells were injected, ganciclovir was administered for 14 days. The retroviral vector that was used only integrated and expressed HSV-Tk1 in proliferating cells, which are killed after a series of metabolic events lead to cell death. The median age of the patients was 11 years (range 2-15 years). Treated brain tumors included seven malignant gliomas, two ependyminomas, and three primitive neuroectodermal tumors. The patients were treated with one of three escalating dose concentrations of vector-producer cells. Four transient central nervous system adverse effects were considered possibly related to the vector-producing cells. In no child did permanent neurological worsening or ventricular irritation develop, and tests for replication-competent retroviruses yielded negative findings.
This Phase I study demonstrates that in vivo gene therapy in which a replication-defective retroviral vector in murine vector-producing cells is delivered by brain injections can be performed with satisfactory safety in a select group of children with localized supratentorial brain tumors.