Recombinant DNA Advisory Committee - 6/9-10/94 
Dr. Roth presented slides demonstrating p53 expression with no effect on bronchial 
epithelial cell proliferation at 7 days. Dr. Haselkom asked if the experiment has been 
performed in combination with cisplatin. Dr. Roth responded that the cisplatin 
experiment has not been performed. Dr. Parkman suggested that the best model for the 
effect of the combination therapy would be to administer these agents to the pleural 
cavity of cotton rats. 
Dr. Roth presented histological data from Balb/c mice experiments involving 
intrabronchial administration of adenovirus constructs. At the highest virus dose (1 x 
IQio PFU), slight evidence of perivascular infiltration was observed with no evidence of 
pneumonia. Dr. Roth quoted a letter from Dr. James Wilson of University of 
Pennsylvania stating that no pathogenicity was observed in 8 subjects receiving 5 x 10^ 
PFU of their adenovirus constructs which have both El and E3 deletions and are more 
pathogenic than the proposed construct in which the E3 gene has been retained. Dr. 
Roth stated that all research-related costs of the trial are underwritten by a sponsored 
research agreement. 
Dr. Roth addressed the possible mechanism of the "bystander effect." Upon transduction 
with the adeno-p53 vector, molecules are secreted from the transduced cells that affect 
killing of the nontranduced cells. These protein molecules have a molecular weight in 
the range between 30 and 100 kilodaltons. These molecules may be released from cells 
undergoing apoptosis. Dr. H. Ginsberg commented that the E3 gene has been reported 
to inhibit apoptosis. 
Dr. Roth noted that there is no shortage of eligible patients for this study. Eligible 
patients will be screened through a conference mechanism. Based on these discussions, 
subjects can make informed decisions regarding protocol participation. 
Responding to concerns about sequential administration of the vector. Dr. Roth said that 
cisplatin could be administered with the first dose of the adeno-p53 vector. 
Dr. Parkman asked whether the clinical trial could be separated for the two groups of 
patients, those with local lesions and those with intrapleural lesions. Additional 
toxicology experiments should be conducted prior to approval of the intrapleural arm of 
the study. Dr. Roth agreed that the two arms of the study could be separated. Dr. 
Parkman favored approval only for the local disease arm of the study. 
Dr. Zallen confirmed that as with other MD Anderson protocols, problems remained 
with Section 1 1 of the Informed Consent document that requires patients to pay for costs 
related to medical care. Dr. Roth reiterated his willingness to work on this issue with 
the IRB. Dr. Parkman suggested that this issue could be clarified by inclusion of a 
statement that patients will not be responsible for any research-related costs; however, 
they may be required to cover some of the costs for treatment. 
Drs. Parkman and H. Ginsberg suggested cotton rats should be used for the toxicology 
studies since they are the most sensitive to adenovirus. However, if the investigators still 
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Recombinant DNA Research, Volume 19 
