Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide.
Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide.
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DOI：
10.1126/scitranslmed.abb6295
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发表时间：
2021-01-06
影响因子：
17.1
通讯作者：
Ebert BL
中科院分区：
文献类型：
--
作者：
Jan M;Scarfò I;Larson RC;Walker A;Schmidts A;Guirguis AA;Gasser JA;Słabicki M;Bouffard AA;Castano AP;Kann MC;Cabral ML;Tepper A;Grinshpun DE;Sperling AS;Kyung T;Sievers QL;Birnbaum ME;Maus MV;Ebert BL
基于细胞的疗法正在成为对抗癌症和其他疾病的有效药物。作为自主的“活药”，这些疗法缺乏精确的控制。嵌合抗原受体(CAR)T细胞可有效靶向血液系统恶性肿瘤，但可迅速增殖并引起毒性。我们使用临床批准的药物来那度胺开发了CAR T细胞的开关，这种药物通过诱导CRL4CRBN E3泛素连接酶和C2H2锌指降解基序之间的相互作用来介导几种目标蛋白的蛋白酶体降解。我们进行了系统的筛选，以识别对来那度胺诱导的降解具有更高敏感度的“超级降解”标签，并使用这些可降解标签来生产可关闭的可降解汽车。为了创造一个ON开关，我们设计了来那度胺诱导的二聚化系统，并开发了需要来那度胺和靶抗原才能激活的分裂CARS。来那度胺的亚治疗浓度控制了开和关CAR T细胞的效应功能。在体内，开关分裂CARS显示出来那度胺依赖的抗肿瘤活性，而开关可降解的CARS被药物治疗耗尽，以限制炎性细胞因子的产生，同时保持抗肿瘤效果。总而言之，这些数据表明，这些来那度胺门控开关是快速、可逆和临床适用的系统，可以在不同的基于基因和细胞的治疗中控制转基因功能。用来那度胺设计了两个化学遗传控制系统来调节CAR T细胞的功能。
Cell-based therapies are emerging as effective agents against cancer and other diseases. As autonomous “living drugs,” these therapies lack precise control. Chimeric antigen receptor (CAR) T cells effectively target hematologic malignancies but can proliferate rapidly and cause toxicity. We developed ON and OFF switches for CAR T cells using the clinically approved drug lenalidomide, which mediates the proteasomal degradation of several target proteins by inducing interactions between the CRL4CRBN E3 ubiquitin ligase and a C2H2 zinc finger degron motif. We performed a systematic screen to identify “super-degron” tags with enhanced sensitivity to lenalidomide-induced degradation and used these degradable tags to generate OFF-switch degradable CARs. To create an ON switch, we engineered a lenalidomide-inducible dimerization system and developed split CARs that required both lenalidomide and target antigen for activation. Subtherapeutic lenalidomide concentrations controlled the effector functions of ON- and OFF-switch CAR T cells. In vivo, ON-switch split CARs demonstrated lenalidomide-dependent anti-tumor activity, and OFF-switch degradable CARs were depleted by drug treatment to limit inflammatory cytokine production while retaining anti-tumor efficacy. Together, the data showed that these lenalidomide-gated switches are rapid, reversible, and clinically suitable systems to control transgene function in diverse gene- and cell-based therapies. Two chemical genetic control systems were engineered to regulate CAR T cell function with lenalidomide.
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影响因子：
10.1
作者：
Hudecek M;Sommermeyer D;Kosasih PL;Silva-Benedict A;Liu L;Rader C;Jensen MC;Riddell SR
通讯作者：
Riddell SR
影响因子：
82.9
作者：
Long, Adrienne H.;Haso, Waleed M.;Shern, Jack F.;Wanhainen, Kelsey M.;Murgai, Meera;Ingaramo, Maria;Smith, Jillian P.;Walker, Alec J.;Kohler, M. Eric;Venkateshwara, Vikas R.;Kaplan, Rosandra N.;Patterson, George H.;Fry, Terry J.;Orentas, Rimas J.;Mackall, Crystal L.
通讯作者：
Mackall, Crystal L.
影响因子：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M
影响因子：
11.2
作者：
Liu X;Ranganathan R;Jiang S;Fang C;Sun J;Kim S;Newick K;Lo A;June CH;Zhao Y;Moon EK
通讯作者：
Moon EK
影响因子：
17.1
作者：
Fischbach MA;Bluestone JA;Lim WA
通讯作者：
Lim WA