July 30, 1990, Hunan Gene Therapy Subconmittee 
III. PROPOSED ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING 
HUMAN GENE THERAPY PROTOCOL ENTITLED "GENE THERAPY OF PATIENTS 
WITH ADVANCED CANCER USING TUMOR INFILTRATING LYMPHOCYTES 
TRANSDUCED WITH THE GENE CODING FOR TUMOR NECROSIS FACTOR": 
Dr. Mclvor presented an overview of the protocol. He said the proposal was more 
complex than the ADA protocol because it sought therapeutic benefit due to gene 
insertion and expression of a very potent biological response modifier whose mechanism 
of action was not completely understood. He noted that some toxicity had been seen in 
using tumor necrosis factor (TNF) in treating cancer patients, but that TNF also showed 
some therapeutic efficacy. He noted there were also problems in this protocol with 
analogous animal models for demonstrating safety and efficacy of the gene transfer and 
expression systems. The safety and efficacy data rely on predictions about TNF 
expression from transduced TILs in relation to toxicity and efficacy of direct TNF 
administration into tumors. Further, there are complications in determining whether an 
efficacious outcome is due to the TIL infusion or due to the fact that TILs are 
transduced with a TNF expression system. 
Dr. Mclvor presented the following questions that needed to be answered relative to this 
proposal: 
1. Do the TNF-TIL maintain their IL-2 dependence after infusion? 
2. Does the 8 mg/kg/day toxicity level pertain to a single injection or to a 
continuous infusion? If both, how is this explained, considering that TNF 
has a half-life of 5-10 minutes? 
3. How much tumor accumulates in mice treated with TNF-transduced cells, 
and how much TNF is expressed in vivo? 
4. Were comparable numbers of TNF-TIL cells infused into the monkeys? 
Were the expression levels the same? Is IL-2 being administered and at 
what level? 
5. Does IL-2 withdrawal result in a drop in TNF-TIL in vivo, and in serum 
TNF? 
6. Do TNF-TIL respond to steroids? 
7. What is the current situation with respect to the availability of anti-TNF 
antibody? 
8. How were the TTL infections performed, considering the low titer of the 
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