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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1261-1269.
Prepublished online as a Blood First Edition Paper on October 16, 2003; DOI 10.1182/blood-2003-08-2908.
Submitted August 25, 2003
Accepted October 6, 2003
Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model
Carolina Berger, C Anthony Blau, Meei-Li Huang, John D Iuliucci, David C Dalgarno, Joelle Gaschet, Shelly Heimfeld, Tim Clackson, and Stanley R Riddell*
Clinical Cooperative Group Hemopoietic Cell Transplantation, GSF-National Research Center of Environment and Health, Munich, Germany
Department of Medicine III, University of Munich, Munich, Germany
Division of Hematology, University of Washington, Seattle, WA, USA
Department of Medicine, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Department of Gene Therapy, Ariad Pharmaceuticals Inc., Cambridge, MA, USA
* Corresponding author; email: sriddell{at}fhcrc.org.
Conditional suicide genes derived from pathogens have been developed to confer drug sensitivity and enhance safety of cell therapy, but this approach is limited by immune responses to the transgene product. We examined a strategy to regulate survival of transferred cells based on induction of apoptosis through oligomerization of a modified human Fas receptor by a bivalent drug (AP1903). Three macaques (Macaca nemestrina) received autologous T cells retrovirally engineered to express a Fas suicide-construct (LV'VFas). High levels of transduced cells were present in blood following cell transfer, but LV'VFas+ cells declined rapidly after AP1903 administration. A small fraction of LV'VFas+ cells resisted elimination by AP1903, in part due to insufficient levels of transgene expression in resting T cells, since reactivation of these cells in vitro enhanced sensitivity to AP1903. An immune response was observed to the transgene product but epitope mapping indicated the response was directed to discrete components of human LV'VFas that were variant with the corresponding macaque sequences. These data demonstrate that chemically induced dimerization can be employed to regulate survival of adoptively transferred T cells in vivo.
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