Human Gene Therapy Subcommittee - July 29-30, 1991 
animals were pre-immunized with the protein antigen from the gene of interest. The 
gene was then introduced into the tumor cells. Five out of six animals showed 
complete regression of their tumors. 
Dr. Epstein noted that the protocol proposes a novel method for gene modification of 
cells. Only twelve mice have been injected to date; of these twelve, only nine 
responded. These experiments employed only one specific tumor type, which is 
different from the type being proposed for treatment in humans. He asked the 
subcommittee to consider if sufficient experiments have been performed in animal 
models. Unlike ex vivo manipulations, the virus is injected into a liposome. In 
experiments using the liposome system with tumor injection, there was evidence of the 
viral DNA in the heart tissue of four of eleven animds, in brain tissue in one of eleven 
animals, and in kidney tissue in two of eleven animals. Therefore, there is a significant 
degree of spread of the virus into other tissues. This is of concern because the 
investigators have shown that the introduction of the constructs into endothelial cells 
generates a local inflammatory response that renders these cells more immunogenic. 
This response may make them more susceptible targets of the immune response. 
Dr. Childress noted that the investigators responded satisfactorily to his comments 
about the patient consent form. The three areas of concern were: (1) There is some 
ambiguity as to what the primary and secondary purposes of the protocol are. This 
ambiguity is carried over to the consent form. There is no need for a rigid separation; 
however, the primary goal will have an impact on risk-benefit analysis. This issue is 
germane to whether the primary benefit is to be expected for current patients or for 
future patients. (2) In the original consent form, the patient was expected to bear what 
appeared to be a heavy financial cost. There has been a clarification; the consent form 
now states that costs related to the research aspect of the protocol will not be borne by 
the patients, but will be covered by the Michigan Clinical Research Center or the 
research grant. To resolve this issue in the consent form, the investigator essentially 
removed the discussion of costs altogether. A discussion of costs should be returned to 
the form with the disclosure statement added, "You will not be expected to bear these 
costs." 
Dr. Walters said Dr. R. Murray would not be present at the meeting and asked the 
subcommittee to read Dr. R. Array's written critique of the protocol. In the critique. 
Dr. R. Murray raised the issue of the efficiency of the transduction procedure within 
the tumor and whether the animal model experiments are sufficient because they are 
not based on a similar type of tumor. 
Dr. Parkman asked the investigators to address the degree to which the consequences 
of the treatment are systemic as opposed to local. 
Dr. Leventhal asked the investigators if they plan to measure all of the tumor masses 
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Recombinant DNA Research, Volume 14 
