Human Gene Therapy Subcommittee - 11/21-22/91 
Dr. Epstein discussed two experiments bearing directly on the proposed human 
experiments. In the first experiment, four of six animals injected with liposomes 
transduced with the H-2K S gene were classified as responders. A responder is defined as 
an animal exhibiting a 50% reduction in tumor diameter. None of the nine control 
animals were classified as responders. In the second experiment, animals were pre- 
immunized with the H-2K S antigen prior to injection of the liposomes into the tumor. 
Five of six animals were classified as responders, with two exhibiting complete tumor 
regression, although microscopic tumor was still detectable. 
Dr. Epstein described experiments that had been performed since the investigators 
presented their original data at the July 29-30, 1991, HGTS meeting. Using an MCA 
106 murine fibrosarcoma and the new PU vector, Vector I, four out of four pre- 
immunized animals were classified as responders; none of five control animals 
responded. When mouse experiments were performed using Vectors II and III 
containing the RSV enhancer, both a reduction in tumor size and prolongation of life 
were observed. Vector II is capable of evoking a systemic CTL response in mice bearing 
the CT26 colon adenocarcinoma. If the in vivo transduction of a murine melanoma 
results in the generation of a CTL response and subsequent reduction in tumor 
metastases, this result would be significant because of the poor immunogenicity of 
melanoma cells. Dr. Epstein noted that Dr. Nabel's data demonstrate a significant 
reduction of pulmonary metastases originating from a melanoma cell line. 
Dr. Epstein said that data exist that liposome-encapsulated DNA may inadvertently 
appear in the heart following intratumor injection. The investigators performed 
additional experiments to investigate this possibility of cardiotoxicity in both mice and 
rabbit animal models. Electrocardiograms and serum creatine kinase assays were 
performed in these animals. No cardiotoxicity was observed. 
Dr. Epstein viewed the proposal as well prepared, embodying a very innovative approach 
to cancer therapy. The investigators responded appropriately to the first review by 
providing results of trials with two additional model systems. The positive results of 
those model systems were sufficient to justify the initiation of Phase I human trials. 
Dr. Epstein raised two points for consideration. First, there is a discrepancy between 
this protocol and the IRB application. The IRB application still refers to 
adenocarcinoma. Second, he asked the investigators for clarification as to the exact 
vector that will be used and the rationale for this choice. 
Review-Dr. R. Murray 
Dr. Walters asked Dr. Epstein to summarize Dr. R. Murray's review in his absence. Dr. 
Epstein said that most of Dr. R. Murray's comments concerned research-related costs to 
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