Intrathecal Gene Therapy for the Treatment of Leptomeningeal Carcinomatosis. National Institutes of Health, Bethesda, Maryland

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Abstract
Leptomeningeal carcinomatosis occurs in 5% to 20% of all cancer patients (9, 18, 22). Among the adult population, most cases of leptomeningeal carcinomatosis are due to breast or lung carcinomas. Over recent years the incidence of leptomeningeal carcinomatosis has been reported to increase, perhaps since cancer patients survive longer with improved systemic therapy (1, 4, 5, 10, 15, 17, 18, 22, 28). Patients with leptomeningeal carcinomatosis have an exceedingly poor prognosis. Whem maximal therapy is tolerated (intrathecal methotrexate and whole-brain irradiation), mean survival is limited to six to seven months (7, 18, 30) and fewer than 15% of the patients are alive at one year (26). Leptoimeningel involvment is not necessarily a premorbid phenomenon, and in two-thirds of cases, it occures when systemic disease is stable or in complete remission (7, 30). In an attempt to improve this grim prognosis or patients with leptomeningeal carcinomatosis, we have developed a novel approach for the treatment of meningeal carcinomatosis. This approach makes use of recombinant DNA technology to transfer a sensitivity gene into the malignant cells seeding the leptomeninges. This is achieved by direct intrathecal injection of cells that actively produce a retroviral vector carrying the herpes simplex thymidine kinase gene (HSV-Tk1) which sensitizes the cells to the antiviral drug ganciclovir. The intrathecally injected producer cells and vector particles can circulate in the CSF and infect cells which are actively synthesizing DNA. In the subarachnoid space, such cells are predominantly tumor cells. The HSV-Tk1 gene is incorporated into the genome of tumor cells and results in expression of the protein encoded by the gene. The enzymatic interaction between HSV-Tk1 and ganciclovir leads to the production of toxic triphosphates of ganciclovir that interfere with DNA synthesis and result in the death of the tumor cells. Since the thymidine kinase enzyme, which is normally present in mammalian cells, has very low affinity for ganciclovir, systemic toxicity related to this mechanism is not expected. This type of in vivo gene transfer has several unique features. First, these retroviral vectors will only integrate into and express their genes in cells which are actively synthesizing DNA. Therefore, non-proliferating normal brain and spinal cord tissue should not acquire the HSV-Tk1 gene and will remain insensitive to ganciclovir. Second, all the transduced tumor cells (and retroviral vector producer cells) will be killed by ganciclovir treatment, reducing the risk of insertional mutagenesis. Third, in this setting, delivery of the producer cells and viral vectors will be facilitated by the normally circulating CSF which bathes the whole surface of the central nervous system (CNS). This clinical trial will evaluate the safety of this approach, assess the dynamics of retroviral vectors in the subarachnoid space, and evaluate the potential antitumor efficacy of the approach. Patients in Group A will receive an intraventricular injection at a dose of 1 × 109 vector producer cells, followed by ganciclovir treatment seven days later for two weeks. Patients in Group B will receive intraventricular and intrathecal injections at a dose of 1 × 109 vector producer cells each (total dose of 2 × 109 HSV-Tk1 cells), followed by ganciclovir treatment seven days later for two weeks. Group C patients will receive intraventricular and intrathecal injections at a dose of 2 × 109 vector producer cells each (total of 4 × 109 HSV-Tk1 cells), followed by ganciclovir treatment seven days later for two weeks. Group D patients will receive intraventricular and intrathecal injecions at a dose of 2 × 109 vector producer cells each, followed three days later by repeat intraventricular and intrathecal injections at the same dose (total dose of 8 × 109 HSV-Tk1 cells), followed by 14 days of ganciclovir beginning on Day 7. CSF samples will be analyzed for vector titers at multiple time points, and if no toxicity is encountered, 12 patients will be treated in Group E of the study with the same parameters as Group D (or any previous group if a maximum tolerated dose below that in Group D is identified). Indications of antitumor efficacy will include monitoring of clinical symptoms, craniospinal MRI evaluation, and CSF analysis for cytology and tumor markers.