Recombinant DNA Advisory Committee - 12/2-3/93 
cells in the CSF in the human trial. He asked the investigators whether there is any data 
demonstrating efficacy of HSV-tk gene transfer and GCV administration on breast and 
lung tumor cells. He concluded that most of his initial concerns were adequately 
addressed, and recommended approval of the protocol. 
Review-Dr. Brinckerhoff 
Dr. Brinckerhoff said that the proposed study is clearly described and thoroughly 
documented. This protocol is a direct extension of previously approved HSV-tk/GCV 
brain tumor studies. Clinical efficacy has been demonstrated in the rat model. Of the 8 
patients treated on Dr. Oldfield's glioblastoma protocol, 5 have demonstrated an 
antitumor response. Injection of the VPC and subsequent GCV administration has been 
well tolerated in all patients; this observation lends strong support for the present 
proposal. Dr. Brinckerhoff posed the following questions. Does the transduction of 
dividing cells in the subarachnoid space include macrophages and epithelial cells as well 
as tumor cells? Are the VPC capable of passing out of the central nervous system, 
circulating in the blood, and eliciting an immune response? Are there possible cryptic 
transcription start sites in the vector construct? She concluded that the proposed study 
could potentially prolong survival of these patients by a relatively non-invasive means 
and may serve as a paradigm for future gene therapy protocols; therefore, the RAC 
should recommend approval. 
Other Comments 
Dr. Leventhal asked whether the proposed number of patients is sufficient to evaluate 
efficacy. Dr. Ram responded that this study is not designed to evaluate efficacy. The 
total number of patients will be divided into 4 dose-escalation groups. 
Investigator Response-Dr. Ram 
Dr. Ram summarized the results obtained from Dr. Oldfield's previously approved 
glioblastoma protocol which is analogous to this study. Twelve patients (10 surgically 
inaccessible and 2 surgically accessible) have received HSV-tk/ganriclovir administration. 
In the surgically accessible group, patients' tumors were resected 1 week following VPC 
injection and subsequently analyzed for in vivo evidence of gene transfer. The objectives 
of the study (i.e., safety, antitumor response, and in vivo gene transfer) were achieved 
and there has been no evidence of immediate or delayed toxicity. Although the study 
was not designed to be curative, significant antitumor responses have been demonstrated. 
A subgroup of patients demonstrated no evidence of antitumor activity, and their tumors 
rapidly progressed for undetermined reasons. Preliminary in situ hybridization assays of 
resected tumors indicate successful gene transfer into tumor cells at the VPC injection 
site. 
Dr. Miller remarked that these glioblastoma patients have a limited life expectancy 
which precludes any observation of long-term safety. Dr. Ram emphasized that the 
proposed leptomeningeal carcinomatosis study will yield valuable scientific information 
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Recombinant DNA Research, Volume 18 
