Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts.
Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts.
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DOI：
10.1038/bcj.2016.61
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发表时间：
2016-08-12
影响因子：
12.8
通讯作者：
Bachmann MP
中科院分区：
文献类型：
--
作者：
Cartellieri M;Feldmann A;Koristka S;Arndt C;Loff S;Ehninger A;von Bonin M;Bejestani EP;Ehninger G;Bachmann MP
CD 19特异性嵌合抗原受体工程化T细胞（CAR T细胞）的过继转移导致了在惰性B细胞恶性肿瘤中令人鼓舞的临床试验。然而，他们也显示了这项迷人技术的局限性：如果CAR T细胞与健康组织发生交叉反应，CAR T细胞甚至可能导致危及生命的肿瘤外、靶向副作用。在这里，我们描述了一种称为UniCAR的新型模块化通用CAR平台技术，该技术通过对CAR T细胞反应性的快速和可逆控制来降低靶向副作用的风险。UniCAR系统由两个组件组成：（1）用于T细胞惰性操作的CAR和（2）用于以个体化时间和靶标依赖性方式重定向UniCAR T细胞的特异性靶向模块（TM）。UniCAR T细胞可以简单地通过替换相应的TM来针对不同的肿瘤靶标进行武装，以（1）同时或随后靶向一种以上的抗原以增强疗效，以及（2）降低治疗中发生抗原丢失肿瘤变体的风险。在这里，我们提供了在体外和体内将UniCAR T细胞重新靶向CD 33和/或CD 123阳性急性髓性白血病母细胞的“概念证明”。
The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide ‘proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo.
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影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M
影响因子：
11.4
作者：
Arndt, C.;Feldmann, A.;Bachmann, M.
通讯作者：
Bachmann, M.
影响因子：
4.4
作者：
Koristka, Stefanie;Cartellieri, Marc;Bachmann, Michael
通讯作者：
Bachmann, Michael
影响因子：
46.9
作者：
Maher, J;Brentjens, RJ;Sadelain, M
通讯作者：
Sadelain, M
影响因子：
12.8
作者：
Ehninger, A.;Kramer, M.;Roellig, C.;Thiede, C.;Bornhaeuser, M.;von Bonin, M.;Wermke, M.;Feldmann, A.;Bachmann, M.;Ehninger, G.;Oelschlaegel, U.
通讯作者：
Oelschlaegel, U.