1. SPECIFIC AIMS 
To apply gene therapy to intracranial tumors we propose a method for in vivo 
gene transfer of the Herpes Simplex thymidine kinase (HS-tk) gene using GlTkSvNa.29 
vector-producing cells. Insertion of the HS-tk gene confers a sensitivity to the anti-herpes 
drug ganciclovir (GCV). We have demonstrated that the direct injection of HS-tk vector- 
producer cells (VPC) into growing tumors in animals can result in their complete 
destruction of the tumor with GCV therapy. This selective destruction of growing tumors 
in situ is thought to result from the transfer of the HS-tk gene into the surrounding tumor 
cells were the production of toxic GCV metabolites within the tumors result from the 
interaction of HS-tk and GCV. This procedure can result in the cure of some 
experimental animals with limited toxicity due to selective gene transfer into tumors. 
Therefore we propose to apply this technique for the treatment of human primary and 
metastatic brain tumors. 
This clinical trial will focus on maximizing the relative number of VPC to the 
tumor mass, along with repeated administration of VPC in an attempt to maximize the 
anti-tumor effect. Adult patients (J> 18 years) with surgically accessible brain tumors will 
be evaluated for the extent and location(s) of their disease before being entered onto 
study. Patients will undergo craniotomy and subtotal resection of the tumor. The tumor 
will than be directly injected with HS-tk VPC, leaving an Ommaya reservoir in place. 
Seven days later additional VPC will be injected through the Ommaya reservoir into the 
tumor bed. One week later GCV will be administered at 5mg/kg/dose IV BID for 14 
days. Two weeks following the completion of the GCV administration additional VPC 
will be instilled. This second cycle of VPC will be given through the Ommaya reservoir 
35 days after operation and 7 days later, the patients will undergo another cycle of 
intravenous therapy with GCV at 5mg/kg/dose BID for 14 days. The patient may receive 
further cycles of VPC and GCV depending upon the initial tumor, response, toxicities, 
clinical status and the radiographic evaluation of their tumors. The patient will then be 
followed every 2-4 weeks after the completion of the final course of GCV. 
This protocol differs from the RAC and FDA approved NIH protocol primarily in 
the surgical technique. Therefore, this protocol may represent a minor modification of 
the NIH protocol. However, we felt it most appropriate to present a new protocol for 
RAC consideration since it will be conducted at two new institutions. The NIH trial 
focuses on the use of stereotaxic surgery with one treatment of multiple injections into a 
small tumor. Patients with larger tumors will likely require multiple treatments of VPC 
for there to be a possibility of complete tumor destruction. Larger tumors will likely 
have a higher fraction of more slowly dividing cells which will require repeated exposure 
to VPC for more complete transduction in vivo. Our proposal utilizing surgical 
debulking and the repeated administration of VPC without the need for repeated 
craniotomy offers an approach for patients who are currently ineligible for the NIH trial 
due to large tumor size. 
[152] 
Recombinant DNA Research, Volume 17 
