Inducible apoptosis as a safety switch for adoptive cell therapy.
Inducible apoptosis as a safety switch for adoptive cell therapy.
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DOI：
10.1056/nejmoa1106152
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发表时间：
2011-11-03
期刊：
影响因子：
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通讯作者：
Brenner MK
中科院分区：
文献类型：
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作者：
Di Stasi A;Tey SK;Dotti G;Fujita Y;Kennedy-Nasser A;Martinez C;Straathof K;Liu E;Durett AG;Grilley B;Liu H;Cruz CR;Savoldo B;Gee AP;Schindler J;Krance RA;Heslop HE;Spencer DM;Rooney CM;Brenner MK
细胞疗法可以在癌症治疗和再生医学中发挥作用，如果有可能在发生不良事件时快速消除注入的细胞。我们设计了一种可诱导的T细胞安全开关，其基于人胱天蛋白酶9与经修饰的人FK结合蛋白的融合，允许有条件的二聚化。当暴露于合成的二聚化药物时，诱导型胱天蛋白酶9（iCasp 9）被激活并导致表达该构建体的细胞快速死亡。我们通过将该基因引入供体T细胞来测试我们的安全开关的活性，该供体T细胞用于增强单倍体相合干细胞移植受体的免疫重建。如果发生移植物抗宿主病（GVHD），患者接受AP 1903，一种生物惰性小分子二聚化药物。我们测量了AP 1903对GVHD以及对含有iCasp 9安全开关的细胞的功能和持久性的影响。5名年龄在3岁至17岁之间的复发性急性白血病患者接受了干细胞移植，并接受了转基因T细胞治疗。在所有五名患者的外周血中检测到细胞，并且尽管其组成性转基因表达，但其数量随时间增加。给四名发生GVHD的患者单剂量二聚化药物，在给药后30分钟内消除了90%以上的修饰T细胞，并结束了GVHD，没有复发。iCasp 9细胞自杀系统可以增加细胞疗法的安全性并扩大其临床应用。（由国家心脏，肺和血液研究所和国家癌症研究所资助; ClinicalTrials.gov编号，NCT 00710892。
Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct. We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch. Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence. The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.)