Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model.
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.
Berger
Carolina
C
Department of Medicine, Klinikum Grosshadern, University of Munich, Germany.
Blau
C Anthony
CA
Huang
Meei-Li
ML
Iuliucci
John D
JD
Dalgarno
David C
DC
Gaschet
Joëlle
J
Heimfeld
Shelly
S
Clackson
Tim
T
Riddell
Stanley R
SR
D019264:Adoptive Transfer / Q000379:methods*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D008254:Macaca nemestrina; D023421:Models, Animal; D008969:Molecular Sequence Data; D009930:Organic Chemicals; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000637:transplantation*; D019076:Transgenes; D019014:fas Receptor / Q000235:genetics* / Q000276:immunology
D003432:Cross-Linking Reagents; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D009930:Organic Chemicals; D019014:fas Receptor; C423866:AP 1903 reagent