CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies.
CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies.
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DOI：
10.1111/jcmm.12810
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发表时间：
2016-07
影响因子：
5.3
通讯作者：
Tonn T
中科院分区：
文献类型：
--
作者：
Romanski A;Uherek C;Bug G;Seifried E;Klingemann H;Wels WS;Ottmann OG;Tonn T
许多 B 细胞急性和慢性白血病往往对自然杀伤 (NK) 细胞的杀伤具有抵抗力。将嵌合抗原受体 (CAR) 引入 T 细胞或 NK 细胞可能会克服这种耐药性。在这里，我们扩展了之前关于恶性淋巴母细胞对 NK-92 细胞（一种持续生长的 NK 细胞系）的耐药性的观察结果，表明抗 CD19-CAR（αCD19-CAR）工程化 NK-92 细胞可以重新获得针对对亲代 NK-92 细胞的细胞溶解活性具有抗性的 CD19 阳性白血病细胞系和原发性白血病细胞的显着细胞毒性。 “第一代”CAR 由 scFv (CD19) 抗体片段生成，与灵活的铰链区、CD3 z 链和 Myc 标签偶联，并克隆到逆转录病毒主干中。未发现 NK-92 和转导的 αCD19-CAR NK-92 细胞针对 CD19 阴性靶标的细胞毒活性存在差异。然而，αCD19-CAR NK-92 细胞特异性且有效地裂解表达 CD19 的 B 前体白血病细胞系以及来自白血病患者的淋巴母细胞。由于 NK-92 细胞在当前的良好生产规范 (cGMP) 条件下可以轻松扩展到临床级数量，并且其安全性已在多项 I 期临床研究中得到记录，因此 CAR 修饰的 NK-92 治疗应被视为淋巴恶性肿瘤患者的治疗选择。
Many B‐cell acute and chronic leukaemias tend to be resistant to killing by natural killer (NK) cells. The introduction of chimeric antigen receptors (CAR) into T cells or NK cells could potentially overcome this resistance. Here, we extend our previous observations on the resistance of malignant lymphoblasts to NK‐92 cells, a continuously growing NK cell line, showing that anti‐CD19‐CAR (αCD19‐CAR) engineered NK‐92 cells can regain significant cytotoxicity against CD19 positive leukaemic cell lines and primary leukaemia cells that are resistant to cytolytic activity of parental NK‐92 cells. The ‘first generation’ CAR was generated from a scFv (CD19) antibody fragment, coupled to a flexible hinge region, the CD3ζ chain and a Myc‐tag and cloned into a retrovirus backbone. No difference in cytotoxic activity of NK‐92 and transduced αCD19‐CAR NK‐92 cells towards CD19 negative targets was found. However, αCD19‐CAR NK‐92 cells specifically and efficiently lysed CD19 expressing B‐precursor leukaemia cell lines as well as lymphoblasts from leukaemia patients. Since NK‐92 cells can be easily expanded to clinical grade numbers under current Good Manufactoring Practice (cGMP) conditions and its safety has been documented in several phase I clinical studies, treatment with CAR modified NK‐92 should be considered a treatment option for patients with lymphoid malignancies.