肿瘤细胞治疗研究
英文原题：CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells.
自体嵌合抗原受体（CAR）-T细胞的临床应用受到可靶向癌症类型有限以及制备过程耗时且成本高昂的制约。
自体嵌合抗原受体（CAR）-T细胞的临床应用因可靶向的癌症类型有限以及生产过程耗时且昂贵而受到限制。我们开发了靶向CD70的、诱导多能干细胞来源的CAR-自然杀伤（NK）（70CAR-iNK）细胞，作为通用免疫细胞治疗的一种方法。除CD70靶向CAR分子外，70CAR-iNK细胞还经CD70基因敲除、高亲和力不可切割CD16（hnCD16）以及白细胞介素（IL）-15受体/IL-15融合蛋白（IL15RF）修饰。多基因编辑的70CAR-iNK细胞对多种肿瘤表现出强效细胞毒性。体内异种移植模型进一步证明其有效靶向淋巴瘤和肾癌的效力。此外，我们发现受者同种异体反应性T细胞高表达CD70，并可被70CAR-iNK细胞清除，从而改善iNK细胞的存活和持久性。凭借肿瘤靶向能力以及清除同种异体反应性T细胞的潜力，70CAR-iNK细胞是下一代通用免疫细胞治疗的有力候选者。
Clinical application of autologous chimeric antigen receptor (CAR)-T cells is complicated by limited targeting of cancer types, as well as the time-consuming and costly manufacturing process. We develop CD70-targeted, induced pluripotent stem cell-derived CAR-natural killer (NK) (70CAR-iNK) cells as an approach for universal immune cell therapy. Besides the CD70-targeted CAR molecule, 70CAR-iNK cells are modified with CD70 gene knockout, a high-affinity non-cleavable CD16 (hnCD16), and an interleukin (IL)-15 receptor /IL-15 fusion protein (IL15RF). Multi-gene-edited 70CAR-iNK cells exhibit robust cytotoxicity against a wide range of tumors. In vivo xenograft models further demonstrate their potency in effectively targeting lymphoma and renal cancers. Furthermore, we find that recipient alloreactive T cells express high levels of CD70 and can be eliminated by 70CAR-iNK cells, leading to improved survival and persistence of iNK cells. With the capability of tumor targeting and the potential to eliminate alloreactive T cells, 70CAR-iNK cells are potent candidates for next-generation universal immune cell therapy.
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