Recombinant DMA Advisory Committee - 6/9-10/94 
In response to Dr. Haselkom's suggestion regarding assigning a patient advocate, Dr. 
Economou stated that neither he nor Dr. Glaspy are of the opinion that a neutrd person 
is necessary to discuss informed consent with patients. The research is secondary to 
patient care and all subjects receive comprehensive information about all research 
protocols for which they are eligible. Subjects are frequently referred to studies other 
than the adoptive immunotherapy trials. 
In response to Dr. Zallen's concerns, Dr. Economou explained that although patients are 
HLA typed, an HLA match is unnecessary because the M24 cell line is used for cytokine 
production and not antigen presentation. Dr. Overell explained that M24 has been used 
in a number of clinical trials at UCLA This cell line is part of a biologies master file 
that Targeted Genetics, Inc., will be filing with the FDA Validation tests are outlined in 
the submission materials. With regard to toxicology studies, experiments are currently 
being conducted in monkeys and mice. In the monkey model, animals receive 
recombinant IL-7. In the murine experiment, animals receive multiple administration of 
irradiated transduced tumor cells. Both of the ongoing animal models will be evaluated 
for evidence of toxicity. Dr. Parkman asked whether there is data documenting 11^7 
induced abnormalities in transgenic mice, e.g., vitiligo (development of white patches in 
skin), or other autoimmune phenomena as a result of responses to the melanin within 
these cells. If such an observation would occur, toxicides should be disclosed in the 
Informed Consent document. 
Dr. Overell responded to Dr. Parkman's question on the rationale for the starting dose 
of 10 ng IL-7/24 hours. This dose is based on data derived from murine experiments 
that included doses between 10 and 100 ng/24 hours. Dr. Parkman expressed concern 
about whether the murine data is an adequate basis for the rationale. The norm for 
other cytokine studies is to determine doses by extrapolation of data from human 
systemic toxicity studies. Dr. Post inquired if the monkey and murine toxicity studies 
have been completed. Dr. Overell said that these studies have recently been initiated. 
The monkey study involves doses 100 times over the dose proposed for the human trial. 
The murine studies will be used to test for autoimmune disease. Dr. Parkman 
commented that these toxicity data are needed for writing a scientifically based Informed 
Consent document. Dr. Smith added that it will be difficult to approve the protocol 
without these toxicity data. Dr. Parkman stressed that this protocol is the first 
application of YLrl to human subjects, and the present proposal is not supported by 
adequate preclinical data. Dr. Noguchi commented that he would agree with Dr. 
Parlmian that FDA would not approve a trial without extensive negotiation regarding the 
study design and data from toxicology experiments. It is entirely appropriate for the 
RAC to raise these concerns. 
Dr. Motulsky said that considering the lack of toxicology studies, he would recommend 
deferral of the protocol until the investigators return to the RAC with these data. Dr. 
Miller asked for clarification regarding the toxicology data that would be required. Dr. 
Parkman inquired whether EL-4 was given to humans systemically before approval of the 
IL-4 gene therapy protocol. Dr. Michael Lotze of the University of Pittsburgh, 
Pittsburgh, Pennsylvania, stated that IL-4 was administered systemically in combination 
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