Recombinant DMA Advisory Committee - 6/9-10/94 
Responding to Dr. Smith's question. Dr. Economou said that data on the effects of 
irradiation on cytokine production has been published in the journal Blood (reprint was 
appended in the submission). The M24 cell line transduced with the EL-7/HyTK 
retroviral vector has stable IL-7 production over 7 days after 10,000 cGy irradiation. Dr. 
McBride stated that 10,000 cGy is more than adequate to inhibit growth of these tumor 
cells. Dr. Smith asked if similar data is available for the primary autologous tumor cells 
and if these cells are clonogenic following irradiation? Dr. Economou responded that 
stable IL^7 production was maintained for greater than 7 days but clonogenic assays were 
not performed. M24 was selected because this cell line has been administered to 
hundreds of patients in polyvalent allogeneic vaccine trials at the University of 
California, Los Angeles (UCLA). For these previous vaccine studies, 5,000 cGy 
irradiation was used and no evidence of tumor growth was observed at this dose. 
In regard to the results of the IL-2 melanoma study. Dr. Economou explained that the 
IL-2 trials were delayed due to a change in the vector supplier. Therefore, both the IL-2 
and IL-7 protocols will be conducted in parallel which would allow for comparisons 
between the two studies. Both studies are similar in design. 
Dr. Economou explained that the animal studies are difficult to perform using a 
preexisting tumor model because these tumors are anaplastic and grow so rapidly that 
the animals die within 3 weeks. There is insufficient time to generate systemic tumor 
specific immunity to control the tumor growth. Perhaps the model system could be 
modified to allow a longer preexisting period and reducing the inoculating tumor dose; 
however, such a modified system would not reflect the clinical situation. He stressed 
that the human study is the only real test of this treatment in which safety and immunity 
will be determined. 
Dr. Parkman stated that the lack of adequate preclinical data is a major weakness in this 
proposal. The previously approved IL-2 study was based on substantial preclinical data 
in an animal model that demonstrated an effect on metastatic tumors. IL-7 is a new 
cytokine and the scientific basis for this study is clearly inadequate. IL-3 is superior to 
IU-7 in preimmunization model experiments. What is the rationale for choosing IL-7? 
Dr. Economou answered that both IL-3 and IU7 demonstrate the most significant 
cytokine effect in animal models. IU3 was not chosen for this study because its biology 
is not well understood. IL-7 is more of a T cell specific cytokine. CD4 and CDS cells 
are largely the cells that are attracted to tumor sites. Dr. Economou explained that his 
laboratory has been studying the effect of IL-7 transduced cells on melanoma for several 
years. Tumor infiltrating lymphocytes isolated from IL-7 transduced tumors demonstrate 
tumor specific cytotoxicity. Dr. Parkman suggested the possibility of using the B16 
melanoma model since B16 was the preexisting tumor model used for the IU2 
preclinical studies. 
Dr. Overell questioned whether the RAC has maintained consistency in its expectations 
regarding preclinical data. Dr. Parkman said that the RAC has consistently required 
demonstration of an antitumor effect in a preexisting tumor model. Clear rationale for 
therapeutic benefit should be demonstrated in preclinical studies even for a Phase I 
Recombinant DNA Research, Volume 19 
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