Development of glypican-3-specific chimeric antigen receptor-modified natural killer cells and optimization as a therapy for hepatocellular carcinoma

作者：Bihui Cao, Qianqian Ni, Zhuxin Chen, Shuo Yang, Xinkui Zhang, Haotao Su, Zhenfeng Zhang, Qi Zhao, Xiaolan Zhu, Manting Liu · 发表于：Journal of Leukocyte Biology · 年份：2024 · DOI：10.1093/jleuko/qiae144 · 被引用次数：17 · 研究领域：Immune Cell Function and Interaction、CAR-T cell therapy research、Immunotherapy and Immune Responses

Hepatocellular carcinoma (HCC) is a highly malignant tumor characterized by insidious onset and rapid progression, with limited treatment choices. One treatment modality, chimeric antigen receptor (CAR)-modified natural killer (NK) cell immunotherapy, has shown promise for various cancers. However, the treatment efficacy of CAR-NK cells for HCC remain inferior. In this study, we developed two glypican-3 (GPC3)-specific CAR-NK-92 cell lines (GPC3-CAR-NK) and explored their antitumor efficacy for the treatment of HCC. Significant levels of cytokine production and in vitro cytotoxicity were produced following co-culture of GPC3+ HCC cells with the developed GPC3-CAR-NK cells. GC33-G2D-NK cells with NK cell-specific signaling domains showed better activation and killing abilities than GC33-CD28-NK cells containing T-cell-specific signaling domains. Moreover, GC33-G2D-NK cells efficiently eliminated tumors in cell-derived xenograft and patient-derived xenograft mouse models. In an abdominal metastasis model, intraperitoneally delivered GC33-G2D-NK cells showed better antitumor ability than intravenously injected cells. Finally, the combination of microwave ablation (MWA) with GC33-G2D-NK cell administration showed greater CAR-NK infiltration and tumor regression in ablated tumors than monotherapy alone. These findings indicate that administration of GPC3-CAR-NK cells may be a potential strategy for the treatment of HCC, and regional delivery or their combination with MWA may optim...