肿瘤细胞治疗研究
英文原题：Non-cleavable hinge enhances avidity and expansion of CAR-T cells for acute myeloid leukemia.
嵌合抗原受体（CAR）T细胞疗法在淋巴系统恶性肿瘤中有效，但在髓系肿瘤中数据有限。
嵌合抗原受体（CAR）T细胞疗法在淋巴系统恶性肿瘤中有效，但在髓系肿瘤中数据有限。在此，我们从基于CD27的CAR靶向CD70（“天然”）治疗急性髓系白血病（AML）开始，发现体内疗效有限，与先前报道一致。随后，我们采用正交方法增强免疫突触两侧的肿瘤和CAR-T细胞结合：一种药理学方法（阿扎胞苷）增加髓系肿瘤中CD70的抗原密度，以及一种工程化方法稳定CAR与CD70的结合。为实现后者，我们设计了一组铰链修饰区域以减轻CD27胞外部分的裂解。我们的CD8铰链和跨膜修饰的CD70 CAR-T细胞不易被裂解，具有增强的结合亲和力，并增加扩增，从而产生更强的体内活性。这种增强的CD70靶向CAR是进一步临床开发的有前景候选者。
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-based CAR to target CD70 ("native") in acute myeloid leukemia (AML), and we find modest efficacy in vivo, consistent with prior reports. We then use orthogonal approaches to increase binding on 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 engineering approach to stabilize binding of the CAR to CD70. To accomplish the latter, we design a panel of hinge-modified regions to mitigate cleavage of the extracellular portion of CD27. Our CD8 hinge and transmembrane-modified CD70 CAR-T cells are less prone to cleavage, have enhanced binding avidity, and increased expansion, leading to more potent in vivo activity. This enhanced CD70-targeted CAR is a promising candidate for further clinical development.
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