Recombinant DNA Advisory Committee - 10/7-8/91 
tumor. Once the tissue culture line has been established, the cytokine gene is 
introduced, the activity is established, safety measures are performed, and then the 
therapy part of the protocol will be performed. The gene-modified cells are injected 
subcutaneously. The draining lymph nodes are removed three weeks later. Then lymph 
node cells are grown in IL-2 and used for therapy. Only terminally ill patients for whom 
there is a previously established cell line with the gene in it will be eligible for the 
protocol. Only at this time will the informed consent form be presented to the patient. 
The patient will be asked to enter this protocol only when they have no other treatment 
options available. 
Dr. Rosenberg addressed the question raised about the nude mouse experiments. If this 
phenomenon is immunologically mediated, why do these tumors not grow in immune 
deficient mice? While immune deficient nude mice still have immune responses and 
have T cell precursors, they can develop normal immune functions. Most human tumors 
transplanted into a nude mouse will not grow because crossing the species barrier is an 
enormous immunologic insult. Even a nude mouse can reject most human tumor 
implants. It is only highly virulent tissue culture lines that can grow regularly in nude 
mice. The vectors to be used, which were approved, have genes encoding for neomycin 
resistance and TNF. Dr. Rosenberg said he could make constructs containing the TK 
gene, that might give an added level of safety, but he stressed that it would be a lot more 
difficult to get a three gene construct to work, because of the promoter inhibition that is 
observed. He said his laboratory attempts to put both the TNF and the IL-2 genes into 
the patient's tumor cells. It is not always successful. The best producer is the one that is 
used. If it happened in one patient that the TNF gene was transduced into a line and 
the IL-2 gene transduced into another, the question would arise as to which one to 
administer. The decision would depend on how many patients had gotten TNF and how 
many had gotten IL-2, since they are limited to five patients for each group. With 
respect to the issue of giving unmodified tumor cells, the NIH IBC had made that a 
strong request. He agreed with the subcommittee that it is not a good idea and the IBC 
has since removed that stipulation. Only the gene-modified tumor cells will be 
administered. The TNF cannot be administered separately from the tumor cells because 
the half-life of the TNF is about four minutes. However, when the tumor cell 
manufactures TNF, there is a continuous bathing of the tumor cells with TNF. There is 
a concentration of all of TNFs immune regulatory properties at the site of the tumor; it 
is a very different situation. 
Dr. Rosenberg addressed the question raised about the cost. At the NIH there is no 
charge for patient care. The costs would come out of the laboratory budget. The 
patients would not be asked to pay anything. He thought that the consent form explains 
the nature of the protocol and the potential risks in simple language, but can be changed 
if necessary. 
Recombinant DNA Research, Volume 15 
[ 24 ] 
I 
