July 30, 1990, Human Gene Therapy Subcommittee 
Dr. Mclvor said the presentation had answered a lot of questions about what the exact 
toxic level was and the routes of administration, but added that it was still difficult to 
predict what difference may be seen in infusion and expression from a cellular source 
rather than an extracellular source. 
3. How much tumor accumulates in the TNF tumor-transduced mice, and 
how much TNF is expressed in vivo ? 
Dr. Mclvor said the tumor studies in mice demonstrated the specificity and role of TNF 
in mediating regression of tumors that are expressing TNF. But he said he was unclear 
as to exactly how much tumor accumulates and how much TNF is secreted in animals 
that have had tumor cells administered. 
Dr. Rosenberg said that he could not answer the question in an exact amount, but that a 
4 millimeter tumor would contain a very large amount of TNF compared to what the 
TIL will make before tumor regression. Dr. Mclvor said that this would equate to about 
a milligram per day. Dr. Rosenberg said that this was true, but the TNF has a very short 
half-life and the tumors don't last long and begin to regress after about 10 days. 
4. In the TNF-TIL infused monkeys were comparable numbers of cells 
infused? Were the expression levels the same? Is IL-2 being administered 
and at what level? 
Dr. Mclvor said that, since data indicate that removal of IL-2 results in a lack of survival 
of TILs, he wondered if the cells would survive in the monkey at all, and what this 
means in terms of the assessment of toxicity in the monkey experiments. 
Dr. Rosenberg said that a main limitation of the monkey model is that the cells are 
human cells in an immunosuppressed monkey. He said he did not believe the human 
cells were likely to survive as long in the monkey as in humans. But he emphasized that 
the amount of TNF made by LAK and TIL which do survive in the presence of IL-2 is 
higher than the starting dose proposed in the protocol. Thus, the investigators do not 
see this as being a major problem. 
Dr. Mclvor asked if the monkeys could be given IL-2. Dr. Rosenberg said it would be a 
major effort to do this. However, he said it potentially could be done. He said his 
feeling was that, since humans had already tolerated higher doses of TNF made in TIL 
and LAK cells, it was not necessary to perform yet another safety study. 
5. Does IL-2 withdrawal result in a drop in TNF-TIL in vivo, and in serum 
TNF? 
Dr. Mclvor said this question was answered in the response to question one. 
Recombinant DNA Research, Volume 14 
[193] 
