Human Gene Therapy Subcommittee - 7/30/90 
2. Effectiveness of a neutralizing antibody in 
neutralizing TNF effects in a murine animal model; and, 
3. Trafficking data on how many TIL cells get to tumors 
and what kind of TIL cell aggregation is expected, so 
as to be able to judge what levels of TNF will be 
secreted. 
Dr. Mahoney said he was interested in organ-specific toxicity of 
TNF in the liver, spleen, and lining of the gut as a result of 
sequestration of TNF which does not reach the tumor. He said he 
also had some minor concerns about the informed consent form. 
Dr. Parkman said he had some concern as to whether local 
production of TNF would actually down-modulate the indigenous 
capacity of TIL cells to kill their appropriate targets, and 
whether the efficacy of the TIL cells was affected by 
introduction of the TNF gene. 
Dr. Leventhal said she wanted to see some dose-response data on 
decreases in toxic effects due to lowering of IL-2 doses and the 
relationship to toxic effects of the TILs themselves. She said 
it was important to know what effects are due to the TNF and what 
are due to the TIL plus the IL-2. Further, she wanted to know 
what methods were envisioned to ameliorate chronic TNF toxicity 
as a result of the TIL infusion should it occur. 
Dr. Walters called on Dr. Rosenberg to respond to the questions 
presented by the subcommittee. Dr. Rosenberg said that the 
protocol was an attempt to improve upon adoptive cellular therapy 
which had begun with LAK cells (treating almost 200 patients) and 
now with TILs, which had demonstrated that almost half the 
patients show an objective regression in their cancers, albeit of 
a limited duration. He said that one obvious way to improve upon 
this result is to try to alter the TIL to improve their anti- 
cancer properties. Dr. Rosenberg said it had been shown in 
previous studies that TIL traffic to tumor deposits and 
concentrate there, and further that indium^^^ studies have 
allowed for calculation of how many cells get to the tumor site. 
He said that calculations have shown that TIL can be used as a 
potential vehicle to deliver TNF to tumors in sufficient quantity 
to improve antitumor effects. 
Dr. Rosenberg said TNF was selected as the first gene to be put 
into TIL on the basis of extensive animal data from experiments, 
looking at biologic and chemotherapeutic effects of TNF in mice. 
It was found to be the most effective agent for causing tumor 
dissolution in the murine model, with dissolution of tumor 
Recombinant DNA Research, Volume 14 
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