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

IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
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
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引用次数: 0

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.

利用双靶向CAR-T疗法推进肝癌治疗。
靶向glypican-3 (GPC3)的嵌合抗原受体(CAR)-T细胞疗法在治疗肝细胞癌(HCC)中显示出前景。然而,仅专注于细胞表面肿瘤相关抗原的CAR-T细胞的疗效往往是有限的。为了克服这一挑战,我们开发了一种双靶向CAR-T细胞策略。细胞内甲胎蛋白(AFP)抗原是一种公认的肝癌生物标志物,它具有免疫原性的人白细胞抗原(HLA)-A*02:01-限制性表位158-166。因此,我们设计了一种具有高特异性和亲和力的T细胞受体(TCR)模拟抗体,为靶向这一关键抗原提供了一种有希望的治疗途径。为了提高肝癌的治疗效果,我们进一步修饰了先前开发的GPC3 CAR-T细胞,使其能够分泌针对呈递的AFP抗原的优化的双特异性T细胞参与器(BiTE)。GPC3 CAR-T细胞对GPC3高的肿瘤细胞具有强大的抗肿瘤功效。这种双靶向策略在体外和体内均显著改善了CAR-T细胞的增殖和持久性,并增强了细胞因子的表达和对HCC细胞的抗肿瘤活性,特别是那些GPC3和AFP表达较低的细胞。我们的发现强调了这种创新方法的潜力,为肝癌患者提供更有效的治疗选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Nanobiotechnology
Journal of Nanobiotechnology BIOTECHNOLOGY & APPLIED MICROBIOLOGY-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
13.90
自引率
4.90%
发文量
493
审稿时长
16 weeks
期刊介绍: Journal of Nanobiotechnology is an open access peer-reviewed journal communicating scientific and technological advances in the fields of medicine and biology, with an emphasis in their interface with nanoscale sciences. The journal provides biomedical scientists and the international biotechnology business community with the latest developments in the growing field of Nanobiotechnology.
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