Recombinant DNA Advisory Committee - 09/14-15/92 
might be transferred as an aerosol? 
What is the relationship between the patient selection process and the informed consent 
process? Should the informed consent document be separated into two sections, one for 
the initial tumor screening process, and one for the protocol? 
Other Comments 
Dr. Parkman noted that patients develop antibody responses to foreign proteins. While 
this response will not be a concern for the initial injections, there is the possibility that 
inflammatory responses will occur from the monthly injections due to the production of 
antibodies to foreign antigens. Since most of these patients will already have some 
degree of tracheal obstruction, what could be the potential effect of an inflammatory 
response in these patients? Will patients be monitored for the presence of circulating 
antibodies to these antigens? Will fetal calf serum be used which could stimulate an 
immune response? 
Dr. Leventhal asked Dr. Roth to address why he chose to use a viral construct instead of 
direct injection of the antisense oligonucleotide. Dr. Post asked if the investigators had 
performed antisense experiments to determine if the observed effects are the result of a 
less specific nonproliferative effect. 
Presentation-Dr. Roth 
Dr. Roth explained that this protocol is designed to treat NSCLC patients who are 
refractory to conventional surgery, radiation therapy, and chemotherapy and exhibit 
significant obstruction of their airway by tumor, such that it is a life threatening process. 
Using topical anesthetic, the bulk tumor will be removed by endoscopy and laser 
techniques. Following tumor resection, the residual microscopic tumor cell bed will be 
injected with retroviral vector supernatants directed against specific genetic abnormalities 
within the tumor cells. Data suggests that these vectors are capable of reversing the 
effect of the dominant oncogene (K-ras) and promoting the effect of the tumor 
suppressor genes (p53). 
Dr. Roth discussed the proposed K-ras antisense mechanism. The dominant oncogene 
family is activated primarily by point mutations, amplifications, or chromosomal 
rearrangement. In the case of K-ras, there is a specific base mutation which allows a 
single allele of that gene to become transformed and produce a hyperactive protein. The 
K-ras antisense construct is specifically designed to reduce the concentration of the 
hyperactive K-ras protein and reverse some of the features of the transformed 
phenotype. A retroviral construct will be used as opposed to an antisense 
oligonucleotide because higher levels of long-term expression can be achieved. Data 
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Recombinant DNA Research, Volume 16 
