肿瘤细胞治疗研究
英文原题：CAR-NK Cells Generated with mRNA-LNPs Kill Tumor Target Cells In Vitro and In Vivo.
CD19-CAR mRNA 和 BCMA-CAR mRNA 被包载入 LNP，分别使 NK 细胞中 CAR 表达率达到 78% 和 95%。
自然杀伤（NK）细胞是先天免疫系统中至关重要的细胞毒性淋巴细胞。通过嵌合抗原受体（CAR）对 NK 细胞进行工程化改造，可使 CAR-NK 细胞更有效地靶向肿瘤抗原。本报告介绍一种新型 CAR mRNA-LNP（脂质纳米颗粒）技术，可有效转染从原代外周血单个核细胞（PBMC）扩增的 NK 细胞，并制备具有功能的 CAR-NK 细胞。将 CD19-CAR mRNA 和 BCMA-CAR mRNA 包装入 LNP 后，分别有 78% 和 95% 的 NK 细胞表达 CAR。使用 CAR mRNA-LNP 转染的 BCMA-CAR-NK 细胞能够杀伤多发性骨髓瘤 RPMI8226 和 MM1S 细胞，并在体外以剂量依赖方式分泌 IFN-γ 和 granzyme B。类似地，使用 CAR mRNA-LNP 制备的 CD19-CAR-NK 细胞可杀伤 Daudi 和 Nalm-6 细胞，并以剂量依赖方式分泌 IFN-γ 和 granzyme B。BCMA-CAR-NK 和 CD19-CAR-NK 细胞的细胞毒性、IFN-γ 和 granzyme B 分泌量均显著高于普通 NK 细胞。此外，CD19-CAR-NK 细胞可在体内显著抑制 Nalm-6 肿瘤生长。因此，可采用 CAR mRNA-LNP 的非病毒递送方式制备抗肿瘤活性强的功能性 CAR-NK 细胞。
Natural killer (NK) cells are cytotoxic lymphocytes that are critical for the innate immune system. Engineering NK cells with chimeric antigen receptors (CARs) allows CAR-NK cells to target tumor antigens more effectively. In this report, we present novel CAR mRNA-LNP (lipid nanoparticle) technology to effectively transfect NK cells expanded from primary PBMCs and to generate functional CAR-NK cells. CD19-CAR mRNA and BCMA-CAR mRNA were embedded into LNPs that resulted in 78% and 95% CAR expression in NK cells, respectively. BCMA-CAR-NK cells after transfection with CAR mRNA-LNPs killed multiple myeloma RPMI8226 and MM1S cells and secreted IFN-gamma and Granzyme B in a dose-dependent manner in vitro. In addition, CD19-CAR-NK cells generated with CAR mRNA-LNPs killed Daudi and Nalm-6 cells and secreted IFN-gamma and Granzyme B in a dose-dependent manner. Both BCMA-CAR-NK and CD19-CAR-NK cells showed significantly higher cytotoxicity, IFN-gamma, and Granzyme B secretion compared with normal NK cells. Moreover, CD19-CAR-NK cells significantly blocked Nalm-6 tumor growth in vivo. Thus, non-viral delivery of CAR mRNA-LNPs can be used to generate functional CAR-NK cells with high anti-tumor activity.
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