A CH2CH3 hinge region enhances the cytotoxicity of anti-CD5 CAR-T cells targeting T cell acute lymphoblastic leukemia
A CH2CH3 hinge region enhances the cytotoxicity of anti-CD5 CAR-T cells targeting T cell acute lymphoblastic leukemia
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DOI：
10.1016/j.intimp.2023.110904
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发表时间：
2023-09-12
影响因子：
5.6
通讯作者：
Chen，Zhiguo
中科院分区：
文献类型：
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作者：
Wu，Huantong;Yu，Yajie;Chen，Zhiguo
嵌合抗原受体T细胞（CAR-T）疗法在B细胞恶性肿瘤患者中显示出相当大的临床疗效，但其在T细胞急性淋巴细胞白血病（T-ALL）患者中的疗效有限。CD 5在大约85%的恶性T细胞上表达，并且靶向CD 5的CAR-T细胞可以表现出针对T-ALL的有效抗肿瘤活性。然而，CAR共刺激内、铰链和跨膜结构域的优化可以进一步增加它们的扩增和持久性，从而增强它们在暴露于肿瘤细胞后的功效。在这里，我们设计了具有不同分子结构的CD 5特异性汽车来产生CAR-T细胞，并研究了它们在体外和体内的抗肿瘤功效。具有4-1BB共刺激结构域（BB.z）或CD 28共刺激结构域（28.z）的CD 5汽车在体外对CD 5+恶性细胞具有特异性细胞毒性。然而，两者都未能延长T-ALL异种移植小鼠的存活时间。随后，我们用CH 2CH 3取代了28.z CAR铰链区，这增强了CH 2CH 3-CD 5 CAR-T细胞在体外和体内特异性根除T-ALL细胞的能力。此外，产生了患者来源的CH 2CH 3-CD 5 CAR-T细胞，其在体外显示出对CD 5阳性急性T-ALL细胞的显著杀伤作用。具有CD 28共刺激结构域和CH 2CH 3铰链区的CD 5 CAR-T细胞的抗肿瘤活性上级具有BB.z和28.z结构域的那些。这些临床前数据为决定CAR-T细胞治疗T-ALL疗效的因素提供了新的见解，并为临床转化提供了希望。
Chimeric antigen receptor T cell (CAR-T) therapies show considerable clinical efficacy in patients with B cell malignancies, but their efficacy is limited in patients with T cell acute lymphoblastic leukemia (T-ALL). CD5 is expressed on ∼85 % of malignant T cells, and CD5-targeting CAR-T cells can exhibit potent antitumor activity against T-ALL. However, optimization of CAR costimulatory endo-, hinge, and transmembrane domains could further increase their expansion and persistence, thereby enhancing their efficacy following exposure to tumor cells. Here we designed CD5-specific CARs with different molecular structures to generate CAR-T cells and investigated their anti-tumor efficacyin vitroandin vivo. CD5 CARs with a 4-1BB costimulatory domain (BB.z) or a CD28 costimulatory domain (28.z) exhibited specific cytotoxicity against CD5+malignant cellsin vitro. However, both failed to prolong the survival of T-ALL xenograft mice. Subsequently, we substituted the 28.z CAR hinge region with CH2CH3, which enhanced the ability of CH2CH3-CD5 CAR-T cells to specifically eradicate T-ALL cellsin vitroandin vivo. Furthermore, patient-derived CH2CH3-CD5 CAR-T cells were generated which showed a marked killing effect of CD5-positive acute T-ALL cellsin vitro. The anti-tumor activity of CD5 CAR-T cells with a CD28 co-stimulation domain and CH2CH3 hinge region was superior to those with BB.z and 28.z domains. These preclinical data provided new insights into the factors dictating efficacy in T-ALL treatment with CAR-T cells and hold promise for clinical translation.