Advancing liver cancer treatment with dual-targeting CAR-T therapy

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.

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Publication Details

Journal
Journal of Nanobiotechnology
Published
2025-06-24
DOI
https://doi.org/10.1186/s12951-025-03512-w
Citations
6
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
6.27

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article

Advancing liver cancer treatment with dual-targeting CAR-T therapy

Meixiao Zhan, Huajing Wang, Dingjie Liu, Xiaopei Li et al.
6 citations
Journal of Nanobiotechnology
CAR-T cell therapy research
6.27
article

Advancing liver cancer treatment with dual-targeting CAR-T therapy

Meixiao Zhan, Huajing Wang, Dingjie Liu, Xiaopei Li, Wei Zhao, Ligong Lu, Bing Liu, Mengmei Zhang, Ermin Xie, Ke He, Xu He, Jiantao Wang, Xiaowen Lin, Xiaowen He, Hongwei Sun, Zhongliang Li, Ze Yang, Ping Jiang, Chao Cheng, Xianyang Li
article en
6 citations

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.

Journal of NanobiotechnologyVol. 23(1)
Jinan University (CN), Guangdong Medical College (CN), University of Macau (MO), Zhuhai People's Hospital (CN), Songshan Lake Materials Laboratory (CN), Lilly (China) (CN)
National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, Guangzhou Municipal Science and Technology Project, Natural Science Foundation of Guangdong Province for Distinguished Young Scholars
Good health and well-being
Openalex Percentile: Top 3%
CAR-T cell therapy research
6.27
DOIOpen Access PDFOpenAlex
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