Human Gene Therapy Subcommittee - 7/30/90 
He said the protocol will be a classic Phase I study which has 
been used for evaluation of a very large number of 
chemotherapeutic agents in patients with advanced cancer. The 
study will begin with a dose of non-selected TIL that has been 
determined to be non- toxic and then will be escalated at 3 -week 
intervals until toxicity is reached. Only after a maximum 
tolerated dose has been reached will selected cells be given, 
dropping back to a level of 1/10 the tolerable dose of non- 
selected TIL, and dropping back to 1/3 the concentration of IL-2 
to be administered. 
Dr. Rosenberg said the initial dose of TIL^j^p to be infused will 
be .07 micrograms of TNF per kilogram. This is approximately 
1/100 the dose of TNF which is maximally tolerable in humans by 
i.v. administration, which is 8 mg/kg per 24 hours. This amount, 
coupled with a half-life of a few minutes, should be less than 
one percent of the safe tolerated dose. Further, non-transduced 
TIL make 20 picograms of TNF per 10® cells, and with high doses 
of IL-2, as many as 6 X 10^^ TIL have been infused into patients, 
thereby producing .2 mg/kg per day of TNF per patient, which is 3 
times the starting dose to be used in the TIL.pj^p protocol. 
Insofar as organ-specific toxicity is concerned, patients have 
already been treated with TILs making more TNF and cleared via 
the same mechanisms without adverse consequences. LAK cells, 
which make 500-600 picograms of TNF per 10® cells, have been 
given to approximately 200 patients, and they are cleared by the 
liver and spleen in an identical fashion to the method of 
clearance of TIL cells. No adverse organ-specific effects have 
been noted. 
Dr. Rosenberg said that after the proposal had been turned down 
by the NCI Clinical Research Committee, the NHLBI Clinical 
Research Committee, and NIH IBC, additional data were gathered 
and some technical changes in the protocol were made which 
resulted in their approving the protocol. The result of this was 
the addendum to the protocol that was supplied to the HGTS. The 
IBC had approved the protocol with three stipulations: 
1. That evidence be presented to show that TNF production 
by the tumor cells was the factor that led to their 
regression; 
2. That studies be performed in an animal model to show 
that tumor regression could be abrogated by use of 
anti -TNF antibody; and, 
3. That safety studies be performed in a primate model. 
Recombinant DNA Research, Volume 14 
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