TY - JOUR
T1 - Improving the safety of T-Cell therapies using an inducible caspase-9 gene
AU - Zhou, Xiaoou
AU - Brenner, Malcolm K.
N1 - Funding Information:
We are thankful to Catherine Gillespie for editing the article. The clinical protocols (I.N.D.13813) were supported by National Institutes of Health–National Heart, Lung and Blood Institute (NIH-NHLBI) Grant U54HL08100 and development of the caspase system by NIH Grants P01CA094237 and P50CA126752. The clinical trials also received support from the Clinical Research Center at Texas Children's Hospital, the Institute for Clinical and Translational Research at Baylor College of Medicine, and shared resources of Dan L Duncan Cancer Center Support Grant P30CA125123.
Publisher Copyright:
© 2016 ISEH - International Society for Experimental Hematology
PY - 2016/11/1
Y1 - 2016/11/1
N2 - Adoptive transfer of T cells can be an effective anticancer treatment. However, uncontrolled or unpredictable immediate or persistent toxic effects are a source of concern. The ability to conditionally eliminate aberrant cells in vivo is therefore becoming a critical step for the successful translation of this approach to the clinic. We review the evolution of safety systems, focusing on a suicide switch that can be expressed stably and efficiently in human T cells without impairing phenotype, function, or antigen specificity. This system is based on the fusion of human caspase-9 to a modified human FK-binding protein, allowing conditional dimerization in the presence of an otherwise bio-inert small molecule drug. When exposed to the synthetic dimerizing drug, the inducible caspase-9 becomes activated, resulting in the rapid apoptosis of cells expressing this construct. We have illustrated the clinical feasibility and efficacy of this approach after haploidentical hematopoietic stem cell transplant. Here we review the benefits and limitations of the approach.
AB - Adoptive transfer of T cells can be an effective anticancer treatment. However, uncontrolled or unpredictable immediate or persistent toxic effects are a source of concern. The ability to conditionally eliminate aberrant cells in vivo is therefore becoming a critical step for the successful translation of this approach to the clinic. We review the evolution of safety systems, focusing on a suicide switch that can be expressed stably and efficiently in human T cells without impairing phenotype, function, or antigen specificity. This system is based on the fusion of human caspase-9 to a modified human FK-binding protein, allowing conditional dimerization in the presence of an otherwise bio-inert small molecule drug. When exposed to the synthetic dimerizing drug, the inducible caspase-9 becomes activated, resulting in the rapid apoptosis of cells expressing this construct. We have illustrated the clinical feasibility and efficacy of this approach after haploidentical hematopoietic stem cell transplant. Here we review the benefits and limitations of the approach.
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U2 - 10.1016/j.exphem.2016.07.011
DO - 10.1016/j.exphem.2016.07.011
M3 - Review article
C2 - 27473568
AN - SCOPUS:84992630807
SN - 0301-472X
VL - 44
SP - 1013
EP - 1019
JO - Experimental Hematology
JF - Experimental Hematology
IS - 11
ER -