Recombinant DNA Advisory Committee - 03/1-2/93 
rate than untransduced cells, and that a CTL response is generated. The investigators 
propose that the delayed growth rate of the tumor cells is a secondary effect of the CTL. 
Dr. Leventhal noted that her written comments to the investigators referred to the fact 
that the data did not demonstrate a diminution or maintenance of tumor growth in an 
immune-competent animal. The data submitted by Dr. Seigler showed that y-IFN 
transduced B16 melanoma cells grow more slowly than untransduced tumor cells in nude 
mice. Dr. Leventhal stated that the murine in vivo data suggests that the slowed growth 
rate of the tumor cells may not be due to the generation of CTL, but to natural killer 
cells or some other mechanism. 
Based on this in vivo data, there is concern about the specific parameters that will be 
monitored in terms of patient response, i.e., the generation of CTL. The investigators 
have not provided data demonstrating that the injection of transduced tumor cells at 1 
site affects the growth of untransduced tumor cells at other sites. Although the murine 
data suggests that transduced cells prevent the occurrence of tumor at other sites when 
injected intravenously, they have not demonstrated any effect on established tumor 
nodules. 
The investigators have agreed that patients must have measurable lesions following the 
removal of the tumor cells for transduction. Dr. Leventhal said that she had requested 
that a statement be included in the informed consent document which explains to the 
patient that tumor cells will be removed in an attempt to perform this experiment; 
however, there is a possibility that they may not receive any injections. 
The endpoints of this study have not been well-defined. The investigators have stated 
that toxicity will be the endpoint; it is unclear how toxicity is defined. They state that 
the development of a granuloma or other vigorous immune response at the site of the 
injection is the desired endpoint. If the generation of CTL will be used as the endpoint, 
the animal data is insufficient to justify this evaluation criterion. 
Review-Dr. Parkman 
Dr. Parkman said that he was concerned about the lack of data demonstrating an anti- 
tumor effect on established tumor. The investigators have indicated that tumor-specific 
CTL can be induced by in vitro stimulation of peripheral blood lymphocytes (PBL) using 
autologous or human leukocyte antigen (HLA)-matched tumors. However, the data 
which was submitted was generated using a cell line. In addition, there is no 
independent control included to demonstrate the nonspecific effect of y-IFN. 
Dr. Parkman stated that his written review asked if there is a minimum amount of y-IFN 
that is necessary to achieve the desired effect. The investigators answered that a 
minimum of 2 units of y-IFN/1 x 10 6 cells/day would be required.. Dr. Parkman noted 
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