文章：

NKG2D-CAR转导的自然杀伤细胞可有效靶向多发性骨髓瘤

NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma

原文发布日期：2021-08-14

DOI: 10.1038/s41408-021-00537-w

类型: Article

开放获取: 是

英文摘要：

CAR-T-cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the antitumor activity of activated and expanded NK cells (NKAE) and CD45RA− T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells were transduced with an NKG2D-4-1BB-CD3z-CAR. CAR-NKAE cells exhibited no evidence of genetic abnormalities. Although memory T cells were more stably transduced, CAR-NKAE cells exhibited greater in vitro cytotoxicity against MM cells, while showing minimal activity against healthy cells. In vivo, CAR-NKAE cells mediated highly efficient abrogation of MM growth, and 25% of the treated mice remained disease free. Overall, these results demonstrate that it is feasible to modify autologous NKAE cells from MM patients to safely express a NKG2D-CAR. Additionally, autologous CAR-NKAE cells display enhanced antimyeloma activity demonstrating that they could be an effective strategy against MM supporting the development of NKG2D-CAR-NK-cell therapy for MM.
 

摘要翻译： 

针对多发性骨髓瘤（MM）的CAR-T细胞疗法目前显示出良好疗效，但通常伴随严重毒性反应。CAR-NK细胞在靶向耐药骨髓瘤细胞时可能表现出较低毒性。通过使用NKG2D等受体，CAR可被设计为识别多种配体，从而获得广泛靶向特异性。本研究通过分析MM患者来源的活化扩增NK细胞（NKAE）及CD45RA⁻ T细胞的抗肿瘤活性验证该策略，这些细胞经基因工程改造可表达基于NKG2D的CAR。NKAE细胞与经辐照的Clone9.mbIL21细胞共培养后，通过载体转导获得NKG2D-4-1BB-CD3z-CAR结构。CAR-NKAE细胞未显示遗传异常证据。尽管记忆T细胞的转导更稳定，但CAR-NKAE细胞对MM细胞表现出更强的体外细胞毒性，同时对健康细胞活性极低。在体内实验中，CAR-NKAE细胞能高效抑制MM生长，25%的治疗小鼠保持无瘤状态。总体而言，这些结果证明改造MM患者自体NKAE细胞安全表达NKG2D-CAR具有可行性。此外，自体CAR-NKAE细胞展现出增强的抗骨髓瘤活性，表明其可能成为对抗MM的有效策略，为推进NKG2D-CAR-NK细胞治疗MM的临床发展提供了支持依据。

原文链接：

NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma