Human Gene Therapy Subcommittee - 7/30/90 
dosage received by each patient. 
Dr. Leventhal asked what the stop criteria would be for dose 
escalation. Dr. Rosenberg said that any grade 4 toxicity that 
were not reversible by appropriate medications would be cause for 
cessation of escalation. 
Dr. Epstein said that the "suicide tumor cells" in the murine 
model are interesting. However, he asked if a better model would 
involve injecting tumor cells into a nude mouse and then 
administering TILs to mirror the human experiment. Dr. Rosenberg 
said that Drs. Mule and Jacob have tried to do this in nude mice, 
BNX mice and SCID mice with no success, due to inability to 
achieve appropriate trafficking of human cells in the mouse. He 
suggested there may be endothelial recognition mechanisms which 
will not allow the human cells to traffic in the mouse. He added 
that such a model would be helpful in evaluating TIL 
subpopulations of gene-modified TIL. 
Dr. Epstein said he was surprised to see the protocol being 
described as a Phase I study and asked where Phase I would end 
and Phase II would begin. Dr. Rosenberg said that "Phase I" was 
a term denoting a trial for determining maximum tolerated doses 
of a therapeutic reagent through dose escalation. He said the 
design of this study was a standard design for such studies. 
Dr. Epstein asked how the subcommittee was to view the trial, 
since up until now the subcommittee had thought that efficacy was 
one of the primary issues to be discussed. By definition, a 
Phase I trial is primarily for determining maximum tolerated 
dose. Dr. Walters said that during the past two years of 
discussion of human gene therapy protocols, the emphasis had gone 
from looking at the protocols as diagnostic studies with no 
emphasis on efficacy, to placing a high emphasis on efficacy in 
the ADA protocol, to now a third category of emphasis on safety, 
but with some attention to efficacy as well. 
Dr. Leventhal said she felt there were two aspects to efficacy in 
a human gene therapy trial: (1) the efficacy of the technique, 
that is, the gene can actually be inserted and one is able to 
determine that insertion took place; and (2) what people normally 
view as efficacy of a treatment, such as the efficacy involved in 
drug or radiation therapy where, despite toxicity, a maximum 
tolerable dose is administered. 
Dr. Epstein said he viewed efficacy as a reasonable expectation 
that a therapy is going to work. He said that what he wanted to 
know is what minimum requirement the RAC and the HGTS were to 
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Recombinant DNA Research, Volume 14 
