Recombinant DMA Advisory Committee - 6/9-10/94 
a tumor suppressor gene, into lung cancer cells to inhibit cell division, i.e., prevent tumor 
growth. The p53 protein forms complexes with normal transcriptional factors that 
control the expression of other genes that promote cell division through the activation of 
DNA synthesis. Cells do not divide in the presence of functional wildtype p53. In the 
absence of wildtype p53, cells divide in an uncontrolled manner. A substantial number 
of NSCLC have been shown to have the defective p53 gene. The investigator proposes 
to replace the defective gene with the corrected p53 gene to inhibit tumor cell division. 
Murine and human lung cells have been transplanted into nude mice and this strategy 
has been demonstrated to be functionally effective. 
This human protocol involves the dehvery of the wildtype human p53 gene to lung 
tumors. The delivery process involves modifying an adenovirus such that early genes 
required for early transcription and DNA replication are replaced with a human wild 
type p53 gene. The adenovirus vector, Ad5CMV-p53, will be injected into NSCIX 
patients. 
The investigators have demonstrated that the addition of cisplatin at the time of 
transduction by the adenovirus-p53 construct induces apoptosis (programmed cell death). 
Cisplatin alone has been shown to reduce growth of tumor cells in culture. The p53 
construct by itself effects a 28% reduction in the cell growth. However, the combination 
of cisplatin and the p53 adenovirus construct have a synergistic effect. This phenomenon 
forms the scientific basis of the human protocol. 
Dr. Haselkorn raised the following questions; (1) What is the scientific explanation for 
the synergistic effect of cisplatin and p53? (2) Since this protocol requires injection into 
a defined tumor, why is the tumor not surgically removed? He said that most of the 
previous concerns raised in the primary written review have been adequately addressed 
by the investigators. 
Review-Dr. Straus (presented by Dr. Haselkorn) 
Dr. Haselkorn summarized Dr. Straus' written comments. Dr. Straus stated that the 
combined treatment of the p53 gene and cisplatin was a potentially exciting Phase I 
study. The investigators propose 2 study groups with up to 21 patients in each group. 
One group will receive direct injection of the adenovirus construct directly into the 
tumor mass. The second group will have the adenovirus construct injected into the 
pleural space (for patients with a pleural disease). Dr. Straus suggested that subjects 
should receive either the adenovirus vector or cisplatin alone as a preliminary toxicity 
study prior to administering the combination. The current 2 week window between 
administration of the adenovirus alone and its use in combination with cisplatin may not 
be adequate to assess toxicity and the potential for adenovirus replication and shedding. 
Immunosuppression caused by cisplatin may augment virus shedding. He suggested that 
a background rate for virus shedding should be determined, and the treatment groups 
and total number of subjects should be reconsidered with this aspect in mind. 
Dr. Straus suggested that the Informed Consent document should be revised with the 
Recombinant DNA Research, Volume 19 
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