Human Gene Therapy Subcommittee - July 29-30, 1991 
Dr. Leventhal agreed that there has to be a good scientific rationale which includes 
preclinical efficacy. There has to be a preclinical model that indicates a reasonable 
probability of success in the treatment in patients. 
Dr. Childress said the protocol was presented in such a way that the boundaries 
between a Phase I and a Phase II study were indistinct. A clear goal of the protocol is 
the examination of efficacy. The HGTS should decide whether sufficient evidence 
exists to support this interest in efficacy. 
Dr. Walters restated the motion to defer approval of the protocol pending the 
submission of data addressing: (1) Polyoma virus sequences in the vector, (2) systemic 
effects of the treatment and characterization of the cytolytic T cells in the spleen, (3) 
HLA-B7 expression in human melanoma cells in tissue culture, and (4) submission of a 
detailed plan outlining the parameters that will be used to analyze long-term follow-up 
in the patients to assess possible autoimmune responses resulting from the treatment. 
Mr. Capron asked to call the question. 
There being no further discussion. Dr. Walters put the motion to a vote. The motion 
passed by a vote of 11 in favor, 0 opposed, and no abstentions. 
IV. PROPOSED ADDITION TO APPENDIX D OF THE NIH GUIDELINES 
REGARDING A HUMAN GENE THERAPY PROTOCOL ENTITLED: GENE 
TRANSFER FOR THE TREATMENT OF CANCER 
Dr. D. Miller said this protocol is a treatment for ovarian cancer localized in the 
peritoneum. It uses a lethally irradiated ovarian teratocarcinoma cell line PA-1, that 
expresses the herpes simplex virus (HSV) thymidine kinase gene (TK). When these 
cells are treated with ganciclovir in vivo, there is a cytotoxic effect on the modified 
cells, as well as neighboring unmodified cells. The postulated mechanism involves 
metabolites of ganciclovir and an immune response against the non-modified cells. 
There is a lack of adequate answers to the Points to Consider. The vectors are not 
described in detail, and a sequence of the vector should be supplied. Another major 
concern is that the packaging cell line, PA-1, has been passaged over 300 times in 
culture. Therefore, the results of tests for adventitious agents must be supplied. Dr. 
D. Miller noted that the cells are to be irradiated prior to administration to the patient, 
and that UV irradiation can lead to subsequent active retrovirus production. 
Additional data concerning this issue are needed. 
Dr. D. Miller said the design of the animal model is problematic with regard to 
possible benefit to the patients. The TK- tumor cells are introduced with the TK+ 
modified tumor cells and then followed by administration of ganciclovir to selectively 
ablate cells. In the most critical experiment performed, a 50-fold excess of TK+ cells 
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Recombinant DNA Research, Volume 14 
