Recombinant DNA Advisoiy Committee - 
administering the therapy until the platelet count comes back to normal, because of 
problems associated with bleeding. However, this would not prevent going ahead and 
retreating the patient after the platelet count had returned to normal. 
He said the reason for a step-wise dose escalation was to introduce an additional level of 
safety into the protocol. It was known that humans could tolerate the higher levels of 
IL-2/IL-4 safely and that there had not been any deaths in patients receiving this 
combination at the high or low doses. TILs do not add substantively to the toxicity 
associated with IL-2 administration. However, since TELs have not been given to 
patients along in combination with II^2/IL-4 at the higher dose it is thought safer to 
introduce a lower dose escalation to err on the side of maximum safety. The decision to 
proceed will be based on, once again, patient safety and if no severe toxicity is associated 
with TIL administration with IL-2/IL-4 at the lower level, then the dose would be 
escalated to the higher level. 
Dr. Anderson said that although Grade IV toxicity is deemed to be associated with life- 
threatening non-reversible toxicity, in cancer patients this is not the rule. Commonly it is 
a result of accrued IL-2 toxicity over time and once administration of IL-2 is stopped, the 
patient's symptoms reverse and within 24 hours the patients are back to near normal. 
Dr. Lotze emphasized that there appear to be dose-response relationships in cancer that 
show that increases in treatment are associated with enhanced response rates. This is 
true also for the use of 11^2 single agent treatment. 
Dr. Walters called for further discussion on the issue of how the homing experiments will 
be performed. Dr. Lotze said the HGTS had raised the question of why these studies 
were being carried out. The reason for doing the studies was to test questions of TILs 
homing and persistence. The consent document as well as the revised protocol clearly 
states that biopsies will be done repeatedly and in fact is the major goal of the protocol. 
Dr. Mclvor said that the subcommittee had voted to approve this protocol with the idea 
in mind that it would come to the RAC with all of the details spelled out on the homing 
and persistence experiments. Further, he did not feel any direct preclinical data had 
been presented to show that the cell marking experiment could work. 
Dr. Lotze reiterated that the major goal of the protocol was to track the cells and try to 
see if they migrate into tumor sites better than in blood or skin. That despite what the 
protocol seemed to say, this was the major goal. As far as preclinical data. Dr. Lotze 
said that information was provided in terms of his previous experience with IL-2 and 11^ 
4 in patients, which was recently published in The Journal of Experimental Medicine^ 
which shows that IL-4 in addition to IL-2 causes enhanced growth of TILs and allows for 
a decrease in the non-specific cytolytic activity. Animal model data for this protocol was 
no better or worse than that for any protocols so far approved. The major problem 
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