A Chemical Switch System to Modulate Chimeric Antigen Receptor T Cell Activity through Proteolysis-Targeting Chimaera Technology
A Chemical Switch System to Modulate Chimeric Antigen Receptor T Cell Activity through Proteolysis-Targeting Chimaera Technology
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DOI：
10.1021/acssynbio.9b00476
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发表时间：
2020-05-15
影响因子：
4.7
通讯作者：
Park, Chi Hoon
中科院分区：
文献类型：
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作者：
Lee, So Myoung;Kang, Chung Hyo;Park, Chi Hoon
尽管嵌合抗原受体（CAR T）细胞疗法具有优异的疗效，但对其安全性的担忧一直在不断增加。CAR T细胞的副作用是由于CAR T细胞活性的异常上调。因此，无论何时患者处于风险中，控制CART细胞活性至关重要。为此目的，已经发明了iCas 9系统，该系统通过化合物的半胱天冬酶-9二聚化诱导CAR T细胞的凋亡，目前正在进行临床试验。然而，iCas 9系统是不可逆的，因为整个CART细胞群从患者体内移除。因此，非常昂贵的CAR T细胞应该在患者从副作用中恢复后重新输注给患者。在这里，我们提出了一种新的CAR T细胞安全策略，其靶向CAR“蛋白质”，而不是CAR“T细胞”。在该系统中，CAR构建体被修饰以携带溴结构域（BD）。在CAR蛋白中添加BD不会干扰原始CAR功能，例如细胞因子分泌和靶细胞裂解。我们的数据显示，使用蛋白水解靶向嵌合体（PROTAC）化合物对抗BD成功地降解了含BD的CAR蛋白。此外，当从细胞中去除PROTAC化合物时，CAR表达恢复，证明我们的系统是可逆的。在靶细胞裂解测定中，PROTAC化合物通过降解CAR蛋白成功地抑制了CAR T细胞的裂解活性。总之，我们开发了一种新的安全系统，其中CAR T细胞可以由化合物“可逆”控制。
Despite the excellent efficacy of chimeric antigen receptor (CAR T) cell therapy, concerns about its safety have been constantly raised. The side effects of CAR T cells result from an aberrantly upregulation of CAR T cell activity. Therefore, it is crucial to control the CART cell activity whenever the patient is at risk. For this purpose, the iCas9 system, which induces apoptosis in CAR T cell through caspase-9 dimerization by compound, has been invented and is currently going under clinical trial. However, the iCas9 system is irreversible, as the entire CART cell population is removed from the patient. Thus, CAR T cells, which are very expensive, should be reinfused to the patients after they recovered from the side-effect. Here, we propose a new CAR T cell safety strategy, which targets CAR "protein", not CAR "T cell". In this system, the CAR construct is modified to bear a bromodomain (BD). The addition of a BD in the CAR protein did not interfere with the original CAR functions, such as cytokine secretion and target cell lysis. Our data showed that the use of a proteolysis-targeting chimaera (PROTAC) compound against BD successfully degraded the BD-containing CAR protein Moreover, the CAR expression is recovered when the PROTAC compound is removed from the cell, demonstrating that our system is reversible. In a target cell lysis assay, the PROTAC compound successfully suppressed the lytic activity of CAR T cells by degrading the CAR protein. In conclusion, we developed a new safety system in which CAR T cells can be "reversibly" controlled by a compound.