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

Object. The outcome for children with recurrent malignant brain tumors is p oor. Thr majority of patients die of progressive disease within months of r elapse, 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 chil dren with recurrent, malignant, supratentorial brain tumors. Methods. After optimal repeated tumor resection, multiple injections of mur ine 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 th e vector-producing cells were injected, ganciclovir was administered for 14 days. The retroviral vector that was used only integrated and expressed HS V-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 (ran ge 2-15 years). Treated brain tumors included seven malignant gliomas, two ependymomas, 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 consider ed possibly related to the vector-producing cells, in no child did permanen t neurological worsening or ventricular irritation develop, and rests for r eplication-competent retroviruses yielded negative Findings. Conclusions. This Phase I study demonstrates that in vivo gene therapy in w hich a replication-defective retroviral vector in murine vector-producing c ells is delivered by brain injections can be performed with satisfactory sa fety in a select group of children with localized supralentorial brain tumo rs.