Recombinant DNA Advisory Committee - 03/1-2/93 
Review— Dr. Hirano 
Dr. Walters called on Dr. Hirano to present her primary review of the protocol 
submitted by Dr. Kenneth W. Culver of Iowa Methodist Medical Center, Des Moines, 
Iowa, and John C. Van Gilder of the University of Iowa, Iowa City, Iowa. 
Dr. Hirano provided a brief overview of the protocol. This study is similar another 
protocol that was submitted by Dr. Edward Oldfield, and approved by the RAC at its 
June 1992 meeting. A retrovirus vector will be used to integrate the gene coding for 
herpes simplex-thymidine kinase (HS-tk) into the brain tumor cells of patients. In turn, 
the HS-tk gene renders these cells sensitive to the antiviral drug ganciclovir (GCV). HS- 
tk will be delivered to the patient's brain tumor cells by direct injection of the murine 
vector producing cells (VPC), PA317. Animal model studies performed in mice, rats, 
and nonhuman primates indicate that no significant toxicity is observed from the direct 
injection of VPC into the brain. 
This study is designed to assess the safety and efficacy of the repeated administration of 
VPC followed by GCV treatment in patients with malignant brain tumors. In addition, 
patients will be monitored for systemic immunity resulting from the repeated injection of 
murine cells. A total of 40 patients will be entered into this study: 20 patients at the 
University of Iowa and 20 patients at Iowa Methodist Medical Center. Patient eligibility 
is limited to those individuals who have surgically accessible brain tumors. 
The investigators propose to administer 3 injections of the VPC, each dose containing 
approximately 1 x l(r cells in a maximum volume of 10 milliliters (ml). Dr. Hirano 
asked the investigators to explain their reason for keeping the number of cells constant 
for all patients rather than proposing a dose escalation. On day 1, patients will undergo 
surgical debulking of their tumor and receive the initial injection of VPC. The second 
injection of cells will be administered on day 7 followed by GCV treatment on day 14; 
the original schema proposed an entire treatment cycle of 2 weeks. However, the 
investigators now propose a revised treatment schema which includes a third injection of 
VPC and subsequent GCV administration. 
Dr. Hirano inquired whether the revised treatment schema is absolute for all patients or 
whether there is some degree of flexibility in the administration schedule. What is the 
possibility that any or all of the patients will require a third injection of VPC and 
subsequent GCV administration? Dr. Culver responded that the treatment schema for 
the first two injections is absolute; however, there will be flexibility in the administration 
of the third injection. If there is evidence of tumor recurrence, then the patient will 
receive the additional treatment. Dr. Hirano said that the schema described by Dr. 
Culver is not clearly outlined in the protocol. 
Recombinant DNA Research, Volume 17 
[65] 
