肿瘤细胞治疗研究
英文原题：Delivery of CD47-SIRPα checkpoint blocker by BCMA-directed UCAR-T cells enhances antitumor efficacy in multiple myeloma.
在复发或难治性多发性骨髓瘤患者的治疗中，BCMA靶向自体CAR-T细胞已显示出优异的抗肿瘤活性。
在复发或难治性多发性骨髓瘤患者的治疗中，靶向 BCMA 的自体 CAR-T 细胞已展现出优异的抗肿瘤活性。然而，其广泛应用受到成本高昂和耗时较长的限制。多发性骨髓瘤细胞高表达 CD47 分子，并与巨噬细胞表面的 SIRP 配体相互作用，通过激活“别吃我”信号逃避巨噬细胞的清除。本研究利用 CRISPR/Cas9 基因编辑系统，开发了一种靶向 BCMA 的通用型 CAR-T 细胞 BC404-UCART，其可分泌 CD47-SIRP 阻断剂。在异种移植模型中，BC404-UCART 细胞显著抑制了肿瘤生长并延长了小鼠的生存期。BC404-UCART 细胞的抗肿瘤活性通过两种机制实现：一方面，UCAR-T 细胞直接杀伤肿瘤细胞；另一方面，BC404-UCART 细胞通过分泌抗 CD47 纳米抗体 hu404-hfc 融合蛋白，阻断巨噬细胞与肿瘤细胞之间的“别吃我”信号，从而增强巨噬细胞的吞噬作用，这为开发治疗多发性骨髓瘤的新型“现货型”细胞免疫疗法提供了潜在策略。
In the treatment of relapsed or refractory multiple myeloma patients, BCMA-directed autologous CAR-T cells have showed excellent anti-tumor activity. However, their widespread application is limited due to the arguably cost and time-consuming. Multiple myeloma cells highly expressed CD47 molecule and interact with the SIRP ligand on the surface of macrophages, in which evade the clearance of macrophages through the activation of "don't eat me" signal. In this study, a BCMA-directed universal CAR-T cells, BC404-UCART, secreting a CD47-SIRP blocker was developed using CRISPR/Cas9 gene-editing system. BC404-UCART cells significantly inhibited tumor growth and prolonged the survival of mice in the xenograft model. The anti-tumor activity of BC404-UCART cells was achieved via two mechanisms, on the one hand, the UCAR-T cells directly killed tumor cells, on the other hand, the BC404-UCART cells enhanced the phagocytosis of macrophages by secreting anti-CD47 nanobody hu404-hfc fusion that blocked the "don't eat me" signal between macrophages and tumor cells, which provides a potential strategy for the development of novel "off-the-shelf" cellular immunotherapies for the treatment of multiple myeloma.
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