Scientific Abstract 
Intrathecal Gene Therapy for the Treatment of Leptomeningeal Carcinomatosis 
Scientific Abstract 
Meningeal carcinomatosis occurs in 5% to 20% of all cancer patients. Most adult cases 
are due to breast or lung carcinomas. Over recent years the incidence of meningeal 
carcinomatosis has been reported to increase, perhaps since cancer patients survive longer 
with improved systemic therapy. Patients with meningeal carcinomatosis have an 
exceedingly poor prognosis. When maximal therapy is tolerated (intrathecal methotrexate and 
whole- brain irradiation) mean survival is limited to 6-7 months and fewer than 15% of the 
patients are alive at one year. In an attempt to improve this grim prognosis of patients with 
leptomeningeal carcinomatosis, we have developed a novel approach for the treatment of this 
disease. 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 (HStk), which sensitizes the cells to the antiviral drug Ganciclovir 
(GCV). The intrathecally injected producer cells and vector particles can circulate in the CSF 
and infect cells that are actively synthesizing DNA. In the subarachnoid space, such cells are 
predominantly tumor cells. The HS-tk gene is incorporated into the genome of tumor cells 
and results in expression of the protein encoded by the gene. The enzymatic interaction 
between HS-tk and GCV leads to the production of toxic triphospates of GCV 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 GCV, 
systemic toxicity related to this mechanism is not expected. 
The proposed clinical trial will evaluate the dynamics of retroviral vectors in the 
subarachnoid space, assess the safety of this approach and evaluate its potential antitumor 
efficacy. This is a dose-escalating study where increasing numbers of producer cells will be 
injected into the ventricular system and the spinal subarachnoid space. Indications of 
antitumor efficacy will include monitoring of clinical symptoms, craniospinal MRI 
evaluation, and CSF analysis for cytology and tumor markers. A total of 20 patients will be 
enrolled in the various phases of the study. 
This is the first clinical attempt to treat meningeal carcinomatosis by in vivo , 
intrathecal, genetic manipulation of the tumor's genome. 
Recombinant DNA Research, Volume 18 
[591] 
