Human Gene Therapy Subcommittee - 7/30/90 
Dr. Walters said he wished to continue with the next agenda item 
before taking a luncheon recess and called on Dr. Mclvor to begin 
the discussion. 
PROPOSED ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING 
HUM7VN 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? 
Recombinant DNA Research, Volume 14 
[77] 
