Recombinant DNA Advisory Committee - 3/3-4/94 
Stimulation. Dr. Roberts said that the cytolytic activity is specific; only cells expressing 
the HIV envelope are killed by the transduced T cells. Dr. Straus expressed his concern 
about the possible systematic effects of cytokines that may be released when large 
numbers of transduced T cells activated by HIV in the blood circulation. The amount of 
cytokine release may be comparable, whether it was triggered through the T cell receptor 
or the CD4-C chimeric receptor. 
Dr. Roberts alluded to studies demonstrating that only those cells expressing HIV 
envelope antigens were killed by activated T cells. The addition of "innocent" cells 
indicated that they were not targets for lysis. Thus, it was concluded that it was unlikely 
that there would be problems associated with nonspecific activity. The use of dose 
escalation studies in patients will allow for careful monitoring of responses. 
Dr. Parkman noted the importance of quantitating cytokine release in order to determine 
a valid starting dose. Dr. Post suggested that the RAC approve a preliminary study on a 
small group of patients at a starting cell dose of 1 x 10^ transduced T cells in order to 
assess toxicity. If 1 x 10^ cells is determined to be a safe dose, the investigators could 
proceed with the dose-escalation study as originally proposed. Dr. Parkman suggested 
that the RAC should require submission of quantitative cytokine release data as a 
stipulation for approval in order to properly assess an adequate cell starting dose. Dr. 
Parkman suggested quantitating the cytokines released by 1 x 10^ activated cells. Dr. 
Straus suggested that patients should be monitored for circulating plasma cytokine levels 
following cell infusion. 
Committee Motion 
The RAC approved a motion made by Dr. Post and seconded by Dr. Smith to accept the 
protocol submitted by Dr. Robert Walker of the NTH, Bethesda, Maryland, by a vote of 
12 in favor, 0 opposed, and 1 abstention. RAC approval of the protocol is contingent on 
review and approval of the following by the primary reviewers: (1) a revised 
experimental design that includes a treatment group that will receive a single 
administration of 1 x 10^ HIV-specific CD8( + ) cells (the number of subjects to be 
determined by the investigator) in addition to the 40 patients who will receive multiple 
doses of between 1 x 10® and 1 x 10^° cells; (2) inclusion of a statement in the protocol 
that addresses possible treatments available in the event of unforseen toxicity, e.g., 
encephalitis; (3) data demonstrating that expression of the universal receptor in a panel 
of primary clinical isolates obtained from HTV( + ) individuals does not increase the 
susceptibility of these cells to HTV infection and data derived from ongoing 14-day 
experiments involving cell proliferation versus viral replication; (4) quantitative data 
derived from in vitro experiments demonstrating the amount of cytokine(s) produced/1 x 
10^ cells/24 hours; (5) inclusion of a statement in the protocol which describes the 
addition of anti-CD4 antibody monitoring; and (6) a revised Informed Consent document 
incorporating modifications submitted by Dr. Carmen and "in the spirit of Mr. G'dali 
Braverman's comments. 
Dr. Walters noted that Dr. Straus abstained from voting on this protocol since he is 
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Recombinant DNA Research, Volume 19 
