小柯机器人

美国马萨诸塞州综合医院Marcela V. Maus研究组发现，不可切割的铰链可增强CAR-T细胞对急性髓系白血病的活性和扩增。相关论文于2022年4月21日在线发表在《癌细胞》杂志上。

研究人员从基于CD27的嵌合抗原受体（CAR）T细胞开始，针对急性骨髓性白血病（AML）的CD70（"原生"），结果发现体内的疗效不大，与之前的报告一致。然后，研究人员使用正交的方法来增加肿瘤和CAR-T细胞在免疫突触两侧的结合：一种药理学方法（阿扎胞苷）来增加骨髓肿瘤中CD70的抗原密度，以及一种工程方法来稳定CAR与CD70的结合。

为了实现后者，研究人员设计了一个铰链修饰区域的组合来减轻CD27细胞外部分的切割。这个CD8铰链和跨膜修饰的CD70 CAR-T细胞不容易被切割，具有更强的结合亲和力和更大的扩展性，从而导致更强的体内活性。这种增强的CD70靶向CAR是进一步临床开发的一个有希望的候选者。

据介绍，CAR T细胞疗法在淋巴性恶性肿瘤中是有效的，但在骨髓类癌症中的数据有限。

附：英文原文

Title: Non-cleavable hinge enhances avidity and expansion of CAR-T cells for acute myeloid leukemia

Author: Mark B. Leick, Harrison Silva, Irene Scarfò, Rebecca Larson, Bryan D. Choi, Amanda A. Bouffard, Kathleen Gallagher, Andrea Schmidts, Stefanie R. Bailey, Michael C. Kann, Max Jan, Marc Wehrli, Korneel Grauwet, Nora Horick, Matthew J. Frigault, Marcela V. Maus

Issue&Volume: 2022-04-21

Abstract: Chimeric antigen receptor (CAR) T cell therapy is effective in lymphoid malignancies,but there has been limited data in myeloid cancers. Here, we start with a CD27-basedCAR to target CD70 (“native”) in acute myeloid leukemia (AML), and we find modestefficacy in vivo, consistent with prior reports. We then use orthogonal approaches to increase bindingon both the tumor and CAR-T cell sides of the immune synapse: a pharmacologic approach(azacitidine) to increase antigen density of CD70 in myeloid tumors, and an engineeringapproach to stabilize binding of the CAR to CD70. To accomplish the latter, we designa panel of hinge-modified regions to mitigate cleavage of the extracellular portionof CD27. Our CD8 hinge and transmembrane-modified CD70 CAR-T cells are less proneto cleavage, have enhanced binding avidity, and increased expansion, leading to morepotent in vivo activity. This enhanced CD70-targeted CAR is a promising candidate for further clinicaldevelopment.

DOI: 10.1016/j.ccell.2022.04.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00157-X

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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