Recombinant DNA Advisory Committee - 12/1-2/94 
negotiated with the FDA. Dr. Samulski noted a published animal study by Dr. James Wilson and his 
colleagues (Philadelphia, Pennsylvania) indicating that there is no gene transduction if the adenovirus vector is 
administered to preimmunized animals; transduced cells are eliminated by the immune responses. Dr. Miller 
said that the human situation may be different since the adenovirus exposure may have happened long ago. In 
addition. Dr. Warren stated that not all the virus administered through the hepatic artery will pass through the 
liver and enter into the systemic circulation. 
Dr. Miller stated that virus stocks should be assayed for oncogenic p53 mutations. Dr. Richard Gregory 
(Canji, Inc.), stated that wild-type p53 is dominant over the mutant p53; the co-transformation assays have 
been performed with the ras oncogene in cells that do not contain wild-type p53. In an endogenous situation 
such as in the Li-Fraumeni syndrome, the wild-type and mutant alleles are expressed at the same level. If the 
mutant p53 is expressed at a high level by virus transduction, the cellular effect may be significant. Dr. 
Walters asked if it is a concern that the vector has an oncogenic p53. Dr. Venook said it is less of a concern 
for patients with advanced cancer, but Dr. Warren agreed to perform the same type of biological assays 
required of other protocols, e.g., the HPV assay. Dr. Bryan Finkle (Canji, Inc.) added that a formal toxicology 
study will be completed before initiating the human trial; such data will be presented to the FDA. 
Dr. Parkman stated that the RAC is equally concerned about the safety data, and the RAC should be careful 
in considering approving a protocol when a large amount of toxicity data is not presented. Mr. Capron 
remarked that the task of monitoring the vector lots can be delegated to the FDA, but the initial deliberation 
of safety testing should be conducted by the RAC. 
Committee Motion 1 
Ms. Meyers made a motion to defer approval of the protocol until the investigators return to the RAC with 
complete toxicology tests in mice and primates, safety testing of p53 mutations, and a detailed description of 
the analyses to be conducted on available post-mortem tissue. Dr. Secundy seconded the motion. Dr. Smith 
added a friendly amendment that the immunized cotton rat experiment should include assessment of toxicity 
and efficiency of transduction. Dr. Parkman emphasized that the toxicity data of immunized versus non- 
immunized permissive hosts, i.e., cotton rats, is required. In addition, the data pertaining to germ line 
integration in non-immunized rats is needed. Dr. Smith asked to review the additional data from the monkey 
experiment. 
Dr. Erickson made a substitute motion to approve the protocol with stipulations to be consistent with other 
approved adeno-p53 protocols. There is some concern about the systemic administration of the vector but a 
similar route of administration has been approved for DNA/liposome complexes. 
Dr. Miller stated that the risk in the present study is greater than other approved protocols: The therapeutic 
gene will be transduced by a virus vector at a high concentration, and there is a concern about the 
unpredictable immune response to the vector. There is a need to review the rat data before approving the 
study. In addition, hepatic artery administration is different from the local injection of the adenovirus vector 
into a tumor mass. Dr. Parkman said that he shared the same concern about safety: There are some 
toxidties from the mouse data, and some effects on normal cells of gene transduction, espedally by the mutant 
p53. These effects are significant in the hepatic artery delivery of the vector. A detailed autopsy plan is 
appropriate for this study, information regarding peripheral persistence and integration after vector 
administration through the hepatic artery is valuable. Dr. Venook agreed that it is the goal of this study to 
obtain information regarding vector distribution. Dr. Finkle stated that similar information will be obtained 
from the primate study, and safety information has been induded in the proposal. Dr. Miller emphasized that 
the critical preimmunized animal data is not available. 
Mr. Capron suggested several changes of the wording of the Informed Consent document, Le., substituting the 
words "therapeutic agent" for "therapeutic drug." The autopsy plan should be specific in regard to questions of 
how to sample the tissue, under what conditions, and what to examine by what tests. Dr. Venook agreed to 
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Recombinant DNA Research, Volume 20 
