自然杀伤 (NK) 细胞的嵌合抗原受体 (CAR) 工程在早期临床研究中显示出有希望的结果。然而，提高CAR-NK细胞的治疗功效势在必行。在本研究中，我们研究了共表达 IL-27 的第四代 CD19 靶向 CAR (CAR.19) 对 NK-92 细胞的影响。我们在体外和异种移植小鼠 B 细胞淋巴瘤模型中观察到 NK-92 细胞增殖和针对 B 细胞癌细胞系的细胞毒性活性显着改善。我们对激活的 NK-92 CAR 变体的系统转录组分析进一步支持了 IL-27 在第四代 CAR 中的潜力，通过提供必要的生长和激活信号来克服基于 NK 细胞的靶向肿瘤治疗的局限性。将 IL-27 整合到 CAR-NK 细胞中成为一种有前途的策略，可以增强其治疗潜力并引发针对癌细胞的强烈反应。这些发现为越来越多的证据做出了重大贡献，支持第四代 CAR 工程在推进基于 NK 细胞的免疫疗法方面的潜力。版权所有 © 2024 国际细胞学会

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells has shown promising results in early-phase clinical studies. However, advancing CAR-NK cell therapeutic efficacy is imperative. In this study, we investigated the impact of a fourth-generation CD19-targeted CAR (CAR.19) coexpressing IL-27 on NK-92 cells. We observed a significant improvement in NK-92 cell proliferation and cytotoxicity activity against B-cell cancer cell lines, both in vitro and in a xenograft mouse B-cell lymphoma model. Our systematic transcriptome analysis of the activated NK-92 CAR variants further supports the potential of IL-27 in fourth-generation CARs to overcome limitations of NK cell-based targeted tumor therapies by providing essential growth and activation signals. Integrating IL-27 into CAR-NK cells emerges as a promising strategy to enhance their therapeutic potential and elicit robust responses against cancer cells. These findings contribute substantially to the mounting evidence supporting the potential of fourth-generation CAR engineering in advancing NK cell-based immunotherapies.Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.