Human Gene Therapy Subcommittee - July 29-30, 1991 
need to use retroviral constructs since the natural gene could be used. The expression 
systems should be redesigned to eliminate retroviral elements that are not necessary. 
Dr. Mclvor asked what other animal experiments could be performed to address the 
issue of the antitumor effect, and the role of the immune and/or inflammatory 
responses in any antitumor effects. One possible experiment would be to administer a 
second challenge with tumor cells. 
Dr. Nabel said that these experiments were in progress. When the preclinical 
experiments were initiated, the efficacy of a retrovirus mediated delivery system versus 
a liposome mediated delivery system was compared. Results with the retroviral vector 
were quite similar to results obtained with liposomes. Amplification of the gene may 
well be occurring, but it does not appear to be a requirement to initiate the antitumor 
or specific cytolytic T cell responses. One advantage of performing the treatment with 
retrovirus sequences is that it would allow for in vivo comparisons of direct retrovirus 
introductions in the future. 
Dr. Parkman said the present protocol has two major weaknesses: (1) the nature of 
the virus, and (2) the lack of documentation of a systemic effect. The HLA-B7 gene 
expression should be analyzed in vitro in human melanoma cells, the target cells to be 
used in the proposed therapy. 
Dr. Parkman moved to defer the protocol until information was obtained regarding the 
following: (1) the vector sequence (if Polyoma sequences are present in the vector, 
their necessity should be justified; and if they are removed, then further experiments 
may be required with the new construct); (2) the systemic effects of the treatment; (3) 
the characterization of cytolytic cells if they are involved; and (4) the data on HLA-B7 
expression in human B7-negative melanomas. Mr. Capron seconded the motion. 
Dr. Leventhal said there needs to be a more organized plan as to how to assess tumor 
size in the patients. How will patients be evaluated for autoimmune disease? Dr. 
Parkman and Mr. Capron accepted this friendly amendment. 
Dr. Nabel said the protocol lists serum enzyme analysis, imaging scans, and anti-DNA 
antibodies as methods used to evaluate these factors. Dr. Leventhal said a more 
detailed plan is required. 
Dr. H. Miller said that in a Phase I study, the risk-benefit evaluation should focus 
primarily on the safety to the patient. \^ile there needs to be an appropriate 
scientific rationale, many scientists would argue that Dr. Nabel has provided such a 
rationale. Dr. H. Miller urged the HGTS not to overemphasize the need for 
confidence about benefit in the first patients who will enter this protocol. The HGTS 
should be careful not to devise a different standard from that which is used for most 
other protocols. 
Recombinant DNA Research, Volume 14 
[897] 
