Recombinant DNA Advisory Committee - 3/3-4/94 
model for the present protocol. 
Considering the lack of a reliable animal model to assess safety, Dr. Post cautioned that 
the investigators should proceed with a conservative approach towards this study, i.e., 
starting at a cell dose of 10^ instead of 10® cells with a small number of patients to assess 
toxicity. Dr. Walker explained that the proposed cell dose of 10® is derived from other 
studies such as Dr. Greenberg's (Protocol #9202-017). Dr. Post said that in that study, a 
consideration has been taken that there is potential difference in toxicity in 
cytomegalovirus (CMV) vs. HIV infection, and a suicide gene has been incorporated in 
the study. 
Dr. Clifford Lane of NIH, Bethesda, Maryland, responded to Dr. Post’s comments that 
there is a significant difference in CMV and HIV infections but it is technically difficult 
to incorporate a suicide gene in the present study. Responding to Dr. Parkman's 
question on side effects. Dr. Lane acknowledged that cortisteroids or other 
immunosuppressive regimens will be considered as first-line intervention in the event of 
unforseen side effects. In response to the RACs concern about committing the valuable 
discordant twin resource to this study, he explained that a statistically significant sample 
size is important in order to obtain definitive information for the preliminary assessment 
of efficacy. This initial information will be used to design future studies that directly 
address efficacy. Dr. Zallen inquired whether there will be enough eligible patients left 
for future studies after enrolling the large number of patients in this Phase I/II study. 
Dr. Lane answered that future studies will be designed using autologous cells obtained 
from HIV-infected individuals; therefore, identical twins will be unnecessary. Dr. Smith 
suggested that perhaps the present trial should be limited to HIV-infected twins with 
CD4 counts below 200. Dr. Lane said that it is important to assess any immune based 
therapy with a spectrum of patients since different outcomes may be observed in patients 
with different immune status. Dr. Lane agreed to decrease the starting dose from 1 x 10® 
to 1 X 10^ cells in response to safety concerns. Dr. Lane described another preliminary 
animal experiment designed to assess safety. Human peripheral blood lymphocytes were 
transplanted into severe combined immunodeficiency mice. Human CD4 counts were 
measured, and no severe destruction of the immune system was observed following 
infusion of the transduced T cells. 
Dr. Margot Roberts of Cell Genesys, Inc., Foster City, California, explained that HIV 
infectivity of transduced T cell experiments are in progress using a panel of primary HIV 
isolates and laboratory HIV strains. In addition, other experiments are being performed 
to assess the antiviral activity of the transduced T cells. Antiviral activity of T cells 
expressing the CD4/C hybrid receptor has been observed toward cells infected with the 
strain IIIB of HIV-1. Dr. Parkman inquired about the cytokine profile of the activated T 
cells. Dr. Roberts explained that the profile of CD4/C hybrid receptor activation is 
similar to activation by the normal T cell receptor, e.g., low levels of gamma-interferon 
(IFN), P-IFN, granulocyte colony stimulating factor (G-CSF), tumor necrosis factor 
(TNF)-a, TNF-P, and 11^4. Dr. Parkman noted that toxicity is often associated with 
certain cytokines, e.g., TNF. Dr. Straus asked whether all or only a small fraction of the 
transduced T cells when infused into patients will be responsive to HIV antigen 
Recombinant DNA Research, Volume 19 
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