The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity.
The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity.
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DOI：
10.1158/2326-6066.cir-14-0127
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发表时间：
2015-02
影响因子：
10.1
通讯作者：
Riddell SR
中科院分区：
文献类型：
--
作者：
Hudecek M;Sommermeyer D;Kosasih PL;Silva-Benedict A;Liu L;Rader C;Jensen MC;Riddell SR
使用合成的嵌合抗原受体（CAR）来重定向T细胞以识别肿瘤，为癌症免疫治疗提供了一种强有力的新方法;然而，确保最佳体内肿瘤识别的汽车的属性仍有待确定。在这里，我们分析了IgG衍生的胞外间隔区结构域的长度和组成对汽车功能的影响。我们的研究表明，具有来自IgG 4铰链-CH 2-CH 3的长间隔区的CD 19-汽车在体外具有功能，但由于间隔区内的Fc结构域与携带Fc受体的骨髓细胞之间的相互作用而缺乏体内抗肿瘤活性，导致活化诱导的T细胞死亡。我们证明，具有长间隔区的CAR-T细胞的体内持久性和抗肿瘤作用可以通过修饰对Fc受体结合至关重要的CH 2结构域中的不同区域来恢复。我们的研究表明，消除与Fc受体结合的修饰对于汽车至关重要，其中长间隔区对于肿瘤识别是必需的，如本文所示的ROR 1特异性CAR。这些结果表明，缺乏内在信号传导功能的细胞外间隔区结构域的长度和组成在汽车的设计中可以是决定性的，以获得最佳的体内活性。
The use of synthetic chimeric antigen receptors (CAR) to redirect T cells to recognize tumor provides a powerful new approach to cancer immunotherapy; however the attributes of CARs that ensure optimal in vivo tumor recognition remain to be defined. Here, we analyze the influence of length and composition of IgG-derived extracellular spacer domains on the function of CARs. Our studies demonstrate that CD19-CARs with a long spacer from IgG4 hinge-CH2-CH3 are functional in vitro but lack antitumor activity in vivo due to interaction between the Fc domain within the spacer and the Fc receptor-bearing myeloid cells, leading to activation-induced T-cell death. We demonstrate that in vivo persistence and antitumor effects of CAR-T-cells with a long spacer can be restored by modifying distinct regions in the CH2 domain that are essential for Fc receptor binding. Our studies demonstrate that modifications that abrogate binding to Fc receptors are crucial for CARs in which a long spacer is obligatory for tumor recognition as shown here for a ROR1-specific CAR. These results demonstrate that the length and composition of the extracellular spacer domain that lacks intrinsic signaling function can be decisive in the design of CARs for optimal in vivo activity.
影响因子：
2.8
作者：
Hudecek M;Anderson LD Jr;Nishida T;Riddell SR
通讯作者：
Riddell SR