A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir

This study has investigated the effects of herpes simplex thymidine kinase gene (HSV-tk) transfer followed by ganciclovir treatment as adjuvant gene t herapy to surgical resection in patients with recurrent glioblastoma multif orme (GBM). The study was open and single-arm, and aimed at assessing the f easibility and safety of the technique and indications of antitumor activit y. In 48 patients a suspension of retroviral vector-producing cells (VPCs) was administered by intracerebral injection immediately after tumor resecti on. Intravenous ganciclovir was infused daily 14 to 27 days after surgery. Patients were monitored for adverse events and for life by regular biosafet y assaying. Tumor changes were monitored by magnetic resonance imaging (MRI ). Reflux during injection was a frequent occurrence but serious adverse ev ents during the treatment period (days 1-27) were few and of a nature not u nexpected in this population. One patient experienced transient neurologica l disorders associated with postganciclovir MRI enhancement. There was no e vidence of replication-competent retrovirus in peripheral blood leukocytes or in tissue samples of reresection or autopsy. Vector DNA was shown in the leukocytes of some patients but not in autopsy gonadal samples. The median survival time was 8.6 months, and the 12-month survival rate was 13 of 48 (27%). On MRI studies, tumor recurrence was absent in seven patients for at least 6 months and for at least 12 months in two patients, one of whom rem ains recurrence free at more than 24 months. Treatment-characteristic image s of injection tracks and intracavity hemoglobin were apparent. In conclusi on, the gene therapy is feasible and appears to be satisfactorily safe as a n adjuvant to the surgical resection of recurrent GBM, but any benefit appe ars to be marginal. Investigation of the precise effectiveness of this gene therapy requires prospective, controlled studies.