Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model

TY - JOUR

T1 - Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model

AU - Berger, Carolina

AU - Blau, C Anthony

AU - Huang, Meei-Li

AU - Iuliucci, John D

AU - Dalgarno, David C

AU - Gaschet, Joëlle

AU - Heimfeld, Shelly

AU - Clackson, Tim

AU - Riddell, Stanley R

PY - 2004/2/15

Y1 - 2004/2/15

N2 - 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, because reactivation of these cells in vitro enhanced sensitivity to AP1903. An immune response to the transgene product was observed, 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 used to regulate survival of adoptively transferred T cells in vivo.

AB - 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, because reactivation of these cells in vitro enhanced sensitivity to AP1903. An immune response to the transgene product was observed, 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 used to regulate survival of adoptively transferred T cells in vivo.

KW - Adoptive Transfer/methods

KW - Amino Acid Sequence

KW - Animals

KW - Apoptosis/drug effects

KW - Cell Survival/drug effects

KW - Cross-Linking Reagents/pharmacology

KW - Epitopes

KW - Epitopes, T-Lymphocyte/immunology

KW - Humans

KW - In Vitro Techniques

KW - Macaca nemestrina

KW - Models, Animal

KW - Molecular Sequence Data

KW - Organic Chemicals

KW - Retroviridae/genetics

KW - T-Lymphocytes/cytology

KW - Transgenes

KW - fas Receptor/genetics

U2 - 10.1182/blood-2003-08-2908

DO - 10.1182/blood-2003-08-2908

M3 - SCORING: Journal article

C2 - 14563634

VL - 103

SP - 1261

EP - 1269

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 4

ER -