Recombinant DNA Advisory Committee - 7/31/90 
terms of consideration of human gene therapy protocols. He 
pointed to the fact that the protocol seeks to express a 
biological response modifier (tumor necrosis factor) in tumor 
infiltrating lymphocytes (TIL ) , and that the mechanism of action 
for this protein is not well understood. Furthermore, it is 
known that TNF has a number of toxic effects associated with it. 
Therefore, there are issues of safety that have to be considered. 
There is relatively minimal preclinical animal data to show the 
protocol is either safe or efficacious. Some in vitro 
experimentation had been done on TNF-transduced TIL, but the 
investigators relied primarily upon observed results in 
administration of TNF by infusion or injection for predicting 
safety and efficacy. 
Dr. Mclvor said that since the patients to be included in the 
protocol were suffering from advanced metastatic cancer, every 
possible consideration to move forward with the new therapy 
should be encouraged. He said the possibility of viral spread 
from TILS into other tissues was an unlikely event. However, he 
noted that if this occurred through some unknown mechanism, it 
could lead to some detrimental effects in the patients. 
Dr. Mclvor said the main risk involved in this therapy is the 
over-expression of TNF in the body that could lead to a toxic 
effect. He noted toxic effects have been seen by administration 
of TNF by injection and infusion at levels of 8 micrograms per 
kilogram per day. The protocol, however, calls for an initial 
level of systemic TNF expression of .07 micrograms per kilogram 
per day, far below the observed toxicity level previously noted. 
He pointed to the fact that TNF expression as a result of 
infusion may be different from cellular expression, but that TIL 
and lymphokine activated killer (LAK) cells both express low 
levels of TNF and have been administered to patients in high 
amount without toxic effects. Therefore, Dr. Mclvor felt it was 
unlikely that a toxic effect would be observed and that the 
procedure was safe. 
Dr. Mclvor said additional primate studies were conducted as a 
result of local review, and initial data indicated that infusion 
of TNF-transduced TILs showed no toxicity. However, he said IL-2 
was not co-administered because of difficulties with IL-2 
administration. Therefore, it was unlikely that a significant 
level of maintenance of the TILs was achieved in the monkeys. It 
did prove that administration of the TIL,j.j^p was not toxic. 
Dr. Mclvor said that if a toxic effect is observed, there are a 
number of options open to the investigators, namely: 
1. Withdrawal of IL-2 administration; 
[ 122 ] 
Recombinant DNA Research, Volume 14 
