Advancing liver cancer treatment with dual-targeting CAR-T therapy
Abstract Chimeric antigen receptor (CAR)-T cell therapy targeting glypican-3 (GPC3) has shown promise in the treatment of hepatocellular carcinoma (HCC). However, the efficacy of CAR-T cells that focus solely on cell surface tumor-associated antigens is often limited. To overcome this challenge, we...
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BMC
2025-06-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03512-w |
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| author | Ze Yang Chao Cheng Zhongliang Li Huajing Wang Mengmei Zhang Ermin Xie Xu He Bing Liu Hongwei Sun Jiantao Wang Xiaopei Li Dingjie Liu Xiaowen Lin Xianyang Li Ping Jiang Ligong Lu Xiaowen He Meixiao Zhan Ke He Wei Zhao |
| author_facet | Ze Yang Chao Cheng Zhongliang Li Huajing Wang Mengmei Zhang Ermin Xie Xu He Bing Liu Hongwei Sun Jiantao Wang Xiaopei Li Dingjie Liu Xiaowen Lin Xianyang Li Ping Jiang Ligong Lu Xiaowen He Meixiao Zhan Ke He Wei Zhao |
| author_sort | Ze Yang |
| collection | DOAJ |
| description | Abstract Chimeric antigen receptor (CAR)-T cell therapy targeting glypican-3 (GPC3) has shown promise in the treatment of hepatocellular carcinoma (HCC). However, the efficacy of CAR-T cells that focus solely on cell surface tumor-associated antigens is often limited. To overcome this challenge, we developed a dual-targeting CAR-T cell strategy. The intracellular alpha-fetoprotein (AFP) antigen, a well-established biomarker of liver cancer, presents the immunogenic Human Leukocyte Antigen (HLA)-A*02:01-restricted epitope 158–166. Consequently, we engineered a T cell receptor (TCR) mimic antibody with high specificity and affinity, providing a promising therapeutic avenue to target this critical antigen. To enhance treatment outcomes for liver cancer, we further modified previously developed GPC3 CAR-T cells, which demonstrated robust anti-tumor efficacy against GPC3-high tumor cells, to secrete an optimized bispecific T cell engager (BiTE) targeting the presented AFP antigen. This dual-targeting strategy significantly improved CAR-T cell proliferation and persistence, as well as enhancing cytokine expression and anti-tumor activity against HCC cells, particularly those exhibiting low GPC3 and AFP expression, both in vitro and in vivo. Our findings highlight the potential of this innovative approach to offer more effective treatment options for patients with liver cancer. Graphical sbstract |
| format | Article |
| id | doaj-art-b71cbca2101e46e2a7b43e6ebaaf9add |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-b71cbca2101e46e2a7b43e6ebaaf9add2025-08-20T03:45:35ZengBMCJournal of Nanobiotechnology1477-31552025-06-0123111510.1186/s12951-025-03512-wAdvancing liver cancer treatment with dual-targeting CAR-T therapyZe Yang0Chao Cheng1Zhongliang Li2Huajing Wang3Mengmei Zhang4Ermin Xie5Xu He6Bing Liu7Hongwei Sun8Jiantao Wang9Xiaopei Li10Dingjie Liu11Xiaowen Lin12Xianyang Li13Ping Jiang14Ligong Lu15Xiaowen He16Meixiao Zhan17Ke He18Wei Zhao19Interventional Medical Treatment Department, Guangzhou First Pepople’s Hospital, the Second Affiliated Hospital, School of Medicine, South China University of TechnologyR&D Department, OriCell Therapeutics Co. LtdGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Clinical Medical College of Jinan University)R&D Department, OriCell Therapeutics Co. LtdThe Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical UniversityR&D Department, OriCell Therapeutics Co. LtdInterventional Medical Treatment Department, Guangzhou First Pepople’s Hospital, the Second Affiliated Hospital, School of Medicine, South China University of TechnologyInterventional Medical Treatment Department, Guangzhou First Pepople’s Hospital, the Second Affiliated Hospital, School of Medicine, South China University of TechnologyGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Clinical Medical College of Jinan University)R&D Department, OriCell Therapeutics Co. LtdR&D Department, OriCell Therapeutics Co. LtdGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Clinical Medical College of Jinan University)Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Clinical Medical College of Jinan University)R&D Department, OriCell Therapeutics Co. LtdInterventional Medical Treatment Department, Guangzhou First Pepople’s Hospital, the Second Affiliated Hospital, School of Medicine, South China University of TechnologyInterventional Medical Treatment Department, Guangzhou First Pepople’s Hospital, the Second Affiliated Hospital, School of Medicine, South China University of TechnologyR&D Department, OriCell Therapeutics Co. LtdInterventional Medical Treatment Department, Guangzhou First Pepople’s Hospital, the Second Affiliated Hospital, School of Medicine, South China University of TechnologyMinimally Invasive Tumor Therapies Center, The Affiliated Guangdong Second Provincial General Hospital of Jinan UniversityInterventional Medical Treatment Department, Guangzhou First Pepople’s Hospital, the Second Affiliated Hospital, School of Medicine, South China University of TechnologyAbstract Chimeric antigen receptor (CAR)-T cell therapy targeting glypican-3 (GPC3) has shown promise in the treatment of hepatocellular carcinoma (HCC). However, the efficacy of CAR-T cells that focus solely on cell surface tumor-associated antigens is often limited. To overcome this challenge, we developed a dual-targeting CAR-T cell strategy. The intracellular alpha-fetoprotein (AFP) antigen, a well-established biomarker of liver cancer, presents the immunogenic Human Leukocyte Antigen (HLA)-A*02:01-restricted epitope 158–166. Consequently, we engineered a T cell receptor (TCR) mimic antibody with high specificity and affinity, providing a promising therapeutic avenue to target this critical antigen. To enhance treatment outcomes for liver cancer, we further modified previously developed GPC3 CAR-T cells, which demonstrated robust anti-tumor efficacy against GPC3-high tumor cells, to secrete an optimized bispecific T cell engager (BiTE) targeting the presented AFP antigen. This dual-targeting strategy significantly improved CAR-T cell proliferation and persistence, as well as enhancing cytokine expression and anti-tumor activity against HCC cells, particularly those exhibiting low GPC3 and AFP expression, both in vitro and in vivo. Our findings highlight the potential of this innovative approach to offer more effective treatment options for patients with liver cancer. Graphical sbstracthttps://doi.org/10.1186/s12951-025-03512-wLiver cancerGlypican-3Alpha-fetoproteinCAR-TBiTE |
| spellingShingle | Ze Yang Chao Cheng Zhongliang Li Huajing Wang Mengmei Zhang Ermin Xie Xu He Bing Liu Hongwei Sun Jiantao Wang Xiaopei Li Dingjie Liu Xiaowen Lin Xianyang Li Ping Jiang Ligong Lu Xiaowen He Meixiao Zhan Ke He Wei Zhao Advancing liver cancer treatment with dual-targeting CAR-T therapy Journal of Nanobiotechnology Liver cancer Glypican-3 Alpha-fetoprotein CAR-T BiTE |
| title | Advancing liver cancer treatment with dual-targeting CAR-T therapy |
| title_full | Advancing liver cancer treatment with dual-targeting CAR-T therapy |
| title_fullStr | Advancing liver cancer treatment with dual-targeting CAR-T therapy |
| title_full_unstemmed | Advancing liver cancer treatment with dual-targeting CAR-T therapy |
| title_short | Advancing liver cancer treatment with dual-targeting CAR-T therapy |
| title_sort | advancing liver cancer treatment with dual targeting car t therapy |
| topic | Liver cancer Glypican-3 Alpha-fetoprotein CAR-T BiTE |
| url | https://doi.org/10.1186/s12951-025-03512-w |
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