Recombinant DNA Advisory Committee - 12/1-2/94 
small font size used for the Points to Consider is unreadable; investigators should succinctly summarize their 
responses with a readable font. She noted the following concerns regarding the preclinical data: (1) Data has 
not been provided demonstrating that all tumor types have receptors for the adenovirus vector. (2) The 
investigators indicate that transduction of the p53 gene induces apoptosis of tumor cells; however, the data are 
indirect and only suggestive of this mechanism. (3) Data has not been submitted demonstrating PCR sensitivity 
capable of detecting 1 x 10 9 replication competent virus particles. Additional data must be provided regarding 
tumor specificity, apoptosis, and PCR sensitivity before recommending approval of the protocol. 
Review-Dr. Haselkorn 
Dr. Haselkorn agreed with the comments presented by Dr. Brinckerhoff. The most significant concern 
regarding this study is the ability of the adenovirus vector to infect the target tumor cells. 
Review-Dr. Secundy 
Dr. Secundy said that the Informed Consent document should provide a clearer description of the number and 
types of procedures that will be conducted, the anticipated time frame for these procedures, the possible risks 
and benefits of the study, and the subject’s responsibility for costs. Will the ability to pay exclude subjects 
from participating in the study? She recommended clarification of the last sentence in the non-technical 
abstract. 
Other Comments 
Dr. Zallen said that the Informed Consent document language relating to costs associated with medical care is 
much improved as compared to other protocols previously submitted by MD Anderson Cancer Center 
investigators. She suggested that the description of the waiting period between surgery and study eligibility 
should be clarified. A 6 week delay is inappropriate. 
Dr. Walters noted that the revised Informed Consent document has clarified the medical cost statement, i.e., 
the experimental treatment and related costs will be provided free to the patients. 
Dr. Parkman asked the investigators to provide additional information regarding in vivo transduction of 
Ad5CMV-p53 in the microscopic residual disease flap model. What is the mechanism of the "bystander" effect 
by which nontransduced cells are killed? 
Dr. Samulski said that introduction of the wild-type p53 gene into tumor cells that contain a p53 mutation is a 
reasonable therapeutic strategy. Multiple p53 mutations have been identified, some of which result in very 
stable p53 proteins. Have the p53 mutations been characterized to determine their effect on tumor cell 
proliferation following wild-type p53 transduction? What are the cellular effects of high level wild-type p53 
protein expression? Dr. Walters noted that the wild-type p53 gene functions as a checkpoint control 
mechanism, causing the cell to rest between cell cycles. 
Dr. Saha said that some individuals are predisposed to tumor development because of a hereditary mutation in 
one allele of the p53 gene. Following a somatic mutation of the second allele, tumors develop. Is preferential 
mutation of the transduced wild-type p53 gene a possibility in predisposed individuals? Dr. Samulski said that 
such mutations are random events, and it is unlikely the transduced gene will result in preferential mutations. 
Dr. Walters remarked that the patients with Li-Fraumeni syndrome have germ line p53 mutations rendering 
them susceptible to tumor development. 
Dr. Smith explained the importance of determining the effect of the transduced wild-type p53 gene on normal 
cells since the vector will transduce normal and tumor cells. Proper autopsy of these subjects would provide 
an opportunity to obtain information regarding the persistence and distribution of adenovirus sequences in 
advanced cancer patients that is not readily available from subjects in CF studies due to a longer life 
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