Recombinant DNA Advisory Committee - 2 / 10 - 11/92 
because it contained a retrovirus. Dr. Greenberg stated that the vector contained no viral 
genes so there was no reason to suspect that the vector would become competent in the 
presence of an HTV infection. 
Dr. Kelley expressed his support for the study. Although conducting animal studies would 
have been advantageous, it is not absolutely necessary. He asked Dr. Greenberg to 
comment on lysis of the cells with ganciclovir used for the treatment of CMV and the risk 
of acute renal failure or other side effects. Dr. Greenberg stated that the investigators 
have extensive experience with T-cell depletion, both in animal models and humans. In 
murine systems, depletion of whole T-cell populations produces no toxicity. Ganciclovir 
treatment of transgenic mice with all mature lymphocytes containing the HSV-TK gene 
causes no toxicity but does ablate the whole T-cell and B-cell compartments. In humans, 
there are extensive data about T-cell depletions with anti-CD3, and some toxicity has been 
observed. With this treatment, only the cells containing the gene should be ablated, which 
is a relatively small population. It is unlikely that ablation might be associated with 
toxicity; however, this issue will be included in the consent form. 
Dr. Geiduschek inquired whether there is an effect on neighboring cells when dying 
lymphocytes are being killed by ganciclovir. Dr. Greenberg said there is no evidence of 
such toxicity except for cells that release cytokines when killed. There is very little 
evidence that the death of cells produces any other toxicity. The best in vivo 
demonstration occurs in transgenic mice where the entire lymphoid compartment expresses 
TK and is ablated by ganciclovir to study the impact on other cells in a lymphoid-depleted 
animal. The animals' cells, including the reticular endothelial system, appear quite normal. 
There is little evidence to suggest that this topic should become an issue. Dr. Geiduschek 
suggested that this response be passed on to the FDA staff. 
Dr. Mclvor brought up another aspect of the protocol regarding AZT administration and 
HSV-TK-positive cells. He inquired whether patients undergoing AZT therapy after the 
T-cell clones are administered would metabolize AZT to a greater extent than patients 
receiving untransduced T-cell clones. Dr. Greenberg stated that there is no evidence that 
there is any difference in AZT sensitivity in the transduced versus the untransduced clones. 
Dr. Doi inquired whether this type of reconstituted response experiment has been 
performed in a model system (not necessarily for this virus, but another antigen) and how 
long the response was maintained. Dr. Greenberg said that there are antigen-specific 
clones in which survival can be monitored. Fifty percent of the activity can be recovered 
within four to six weeks after the infusion. Post-infusion cells persist for a long time and 
are effective in reconstituting immunity. Many laboratories have shown that T-cells are 
not really immunogens. It is difficult to elicit significant immune responses to T-cells even 
in the presence of an allogenic graft-versus-host (GVH) response. Even with GVH, these 
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Recombinant DNA Research, Volume 15 
