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Updated: Jun 23, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Development of glypican-3-specific chimeric antigen receptor-modified natural killer cells and optimization as a
Bihui Cao1,2,3, Qianqian Ni4, Zhuxin Chen1,2
1Department of Cardiac Surgery, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China.
Abstract:
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 optimize their efficacy against HCC and may have translational value.
Insights
Chimeric antigen receptor (CAR)-modified natural killer (NK) cell therapy shows promise for hepatocellular carcinoma (HCC). Glypican-3 (GPC3)-specific CAR-NK cells effectively target and eliminate HCC tumors in preclinical models, suggesting a potential new treatment strategy.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Hepatocellular carcinoma (HCC) is a deadly cancer with limited treatment options.
- Chimeric antigen receptor (CAR)-modified natural killer (NK) cell immunotherapy shows potential but has limitations in HCC treatment efficacy.
Purpose of the Study:
- To develop glypican-3 (GPC3)-specific CAR-NK-92 cell lines for HCC treatment.
- To evaluate the antitumor efficacy of these novel GPC3-CAR-NK cells against HCC.
Main Methods:
- Development of two GPC3-specific CAR-NK-92 cell lines (GPC3-CAR-NK).
- In vitro assessment of cytokine production and cytotoxicity against GPC3+ HCC cells.
- In vivo evaluation in cell-derived and patient-derived xenograft mouse models, including abdominal metastasis and combination therapy with microwave ablation (MWA).
Main Results:
- GPC3-CAR-NK cells demonstrated significant cytokine production and cytotoxicity against HCC cells.
- GC33-G2D-NK cells, utilizing NK cell-specific signaling, outperformed GC33-CD28-NK cells in activation and killing.
- GC33-G2D-NK cells effectively reduced tumors in mouse models, with intraperitoneal delivery showing superior results in metastasis models.
- Combination therapy with MWA enhanced CAR-NK infiltration and tumor regression.
Conclusions:
- GPC3-CAR-NK cells represent a promising strategy for HCC treatment.
- Regional delivery and combination with MWA may enhance the therapeutic efficacy of CAR-NK cells for HCC.
