Recombinant DNA Advisory Committee - 12/2-3/93 
passage cells, which are more relevant to the human study. Dr. Geiduschek suggested 
the RAC might condition its approval on optimization of the transduction efficiency and 
IL-4 production. Dr. Kraus agreed to accept a minimum production level of 50 
picograms (pg) of IL-4/10 6 cells/ml/24 hours. 
Dr. Leventhal suggested the inclusion of a stopping rule that if the investigators are 
unable to transduce cells at the minimum level of IL-4 production in 3 of the first 6 
patients, the investigators are not permitted to treat any additional patients until they 
return to the full RAC for discussion of the data. Dr. Chang said that a range of IL4 
expression would allow for a dose-response assessment. Dr. Parkman responded that a 
10-fold lower level of IL-4 expression resulted in antitumor responses in the animal 
model; therefore, the level of IL-4 secretion stipulated by Dr. Geiduschek is acceptable. 
Committee Motion 
A motion was made by Dr. Leventhal and seconded by Dr. Carmen to approve the 
protocol. Approval of the protocol is contingent on submission of the following: (1) 
data demonstrating optimization of cell transduction in early passage human melanoma 
cells and a minimum level of IL-4 secretion 50 pg of IL-4/10 6 cells/ml/24 hours), and 
(2) inclusion of a stop criterion that if the investigators are unable to transduce cells at 
the minimum level of IL-4 secretion in 3 of the first 6 patients enrolled in the study, the 
investigators will not be permitted to treat additional patients without returning to the 
full RAC for discussion of the data. The motion to approve the protocol passed by a 
vote of 12 in favor, 3 opposed, and 1 abstention. 
XVIII. UPDATE ON THE HUMAN GENE TRANSFER PROTOCOL ENTITLED: A PHASE I 
STUDY, IN CYSTIC FIBROSIS PATIENTS, OF THE SAFETY, TOXICITY, AND 
BIOLOGICAL EFFICACY OF A SINGLE ADMINISTRATION OF A REPLICATION - 
DEFICIENT RECOMBINANT ADENOVIRUS CARRYING THE cDNA OF THE 
NORMAL HUMAN CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE 
REGULATOR GENE IN THE LUNG /DR. CRYSTAL 
Dr. Crystal presented a progress report on his ongoing CF protocol. He stated that the 
CFTR gene has been successfully delivered to the airway epithelium using an El- and 
E3-deleted adenovirus vector. Both in vitro and in vivo expression of the CFTR gene has 
been demonstrated. Possible safety concerns are over-expression of the inserted gene, 
inflammation, immune reactions, generation of replication-competent virus, 
complementation, recombination, germ line transfer, and virus shedding. In animal 
studies involving rhesus monkeys, doses ranging between 10 and 100 times of those doses 
proposed for the human study demonstrated no acute or chronic clinical sequelae. Four 
patients have been treated on the human study to date. No adverse reactions were 
encountered with intranasal administration of the vector in any of these patients. These 
patients underwent delivery to the lower lobe of one side of the lung by a fiberoptic 
bronchoscope. One patient received a dose of 2 x 10 6 cfu, 2 patients received 2 x 10 7 
cfu, and 1 patient received 2 x 10 9 cfu. 
Recombinant DNA Research, Volume 18 
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