文章：

具有广泛抗肿瘤活性的CD126 CAR-T细胞的临床前开发

Preclinical development of CD126 CAR-T cells with broad antitumor activity

原文发布日期：2021-01-04

DOI: 10.1038/s41408-020-00405-z

类型: Article

开放获取: 是

英文摘要：

Chimeric antigen receptor T (CAR-T) cell therapy is a transformative approach to cancer eradication. CAR-T is expensive partly due to the restricted use of each CAR construct for specific tumors. Thus, a CAR construct with broad antitumor activity can be advantageous. We identified that CD126 is expressed by many hematologic and solid tumors, including multiple myeloma, lymphoma, acute myeloid leukemia, pancreatic and prostate adenocarcinoma, non-small cell lung cancer, and malignant melanoma among others. CAR-T cells targeting CD126 were generated and shown to kill many tumor cells in an antigen-specific manner and with efficiency directly proportional to CD126 expression. Soluble CD126 did not interfere with CAR-T cell killing. The CAR-T constructs bind murine CD126 but caused no weight loss or hepatotoxicity in mice. In multiple myeloma and prostate adenocarcinoma xenograft models, intravenously injected CD126 CAR-T cells infiltrated within, expanded, and killed tumor cells without toxicity. Binding of soluble interleukin-6 receptor (sIL-6R) by CAR-T cells could mitigate cytokine release syndrome. Murine SAA-3 levels were lower in mice injected with CD126 CAR-T compared to controls, suggesting that binding of sIL-6R by CAR-T cells could mitigate cytokine release syndrome. CD126 provides a novel therapeutic target for CAR-T cells for many tumors with a low risk of toxicity.
 

摘要翻译： 

嵌合抗原受体T（CAR-T）细胞疗法是一种革命性的癌症根除方法。CAR-T治疗费用高昂的部分原因是每种CAR结构仅能用于特定肿瘤。因此，具有广谱抗肿瘤活性的CAR结构更具优势。我们发现CD126在多种血液肿瘤和实体瘤中均有表达，包括多发性骨髓瘤、淋巴瘤、急性髓系白血病、胰腺癌和前列腺腺癌、非小细胞肺癌及恶性黑色素瘤等。靶向CD126的CAR-T细胞不仅能以抗原特异性方式杀伤多种肿瘤细胞，且其效率与CD126表达水平呈正相关。可溶性CD126不会干扰CAR-T细胞的杀伤作用。该CAR-T结构可与小鼠CD126结合，但未引起小鼠体重减轻或肝毒性。在多发性骨髓瘤和前列腺腺癌异种移植模型中，静脉注射的CD126 CAR-T细胞能浸润肿瘤组织、扩增并杀伤肿瘤细胞，且不产生毒性。CAR-T细胞与可溶性白细胞介素-6受体（sIL-6R）的结合可缓解细胞因子释放综合征。与对照组相比，注射CD126 CAR-T细胞的小鼠血清淀粉样蛋白A-3（SAA-3）水平更低，这表明CAR-T细胞通过结合sIL-6R缓解了细胞因子释放综合征。CD126为CAR-T细胞治疗多种肿瘤提供了新型治疗靶点，且具有低毒性风险。

原文链接：

Preclinical development of CD126 CAR-T cells with broad antitumor activity