Glypican-3靶向肝细胞癌治疗的进展与挑战
Progress and challenges in glypican-3 targeting for hepatocellular carcinoma therapy
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影响因子:4.4
分区:医学2区 / 药学2区
发表日期:2024 Oct
作者:
Arnaud Couzinet, Toshihiro Suzuki, Tetsuya Nakatsura
DOI:
10.1080/14728222.2024.2416975
摘要
Glypican-3（GPC3）是一种细胞膜锚定的肝素硫酸蛋白多糖，近年来因其在多种癌症中的高表达，尤其是肝细胞癌（HCC），以及在成人正常组织中的有限表达，成为癌症抗原的研究焦点。在此，我们基于GPC3肽疫苗对HCC的研究经验，提出GPC3作为癌症抗原的潜力，已开发出从临床前研究到首次人体试验的疫苗。在本综述中，我们总结了近年来针对GPC3的免疫治疗的现状及未来前景，重点包括临床试验；肽疫苗、mRNA疫苗、抗体治疗以及嵌合抗原受体/T细胞受体（CAR/T细胞）疗法，并讨论了通过免疫疗法有效消灭HCC的其他策略。GPC3是HCC免疫治疗的理想抗原。在可切除HCC中，利用生理免疫监视、免疫检查点抑制剂和GPC3靶向癌症疫苗的免疫疗法，在预防复发方面显示出前景，有望作为预防性佐剂治疗。然而，在晚期HCC中，临床试验尚未展现出足够的抗肿瘤效果，与临床前研究形成对比。逆向转化（bedside-to-bench）研究对于识别阻碍GPC3靶向免疫疗法的因素至关重要。
Abstract
Glypican-3 (GPC3) is a cell membrane-anchored heparan sulfate proteoglycan that has recently garnered attention as a cancer antigen owing to its high expression in numerous cancers, particularly hepatocellular carcinoma (HCC), and to limited expression in adult normal tissue.Here, we propose the potential of GPC3 as a cancer antigen based on our experience with the GPC3 peptide vaccine against HCC, having developed a vaccine that progressed from preclinical studies to first-in-human clinical trials. In this review, we present a summary of the current status and future prospects of immunotherapies targeting GPC3 by focusing on clinical trials; peptide vaccines, mRNA vaccines, antibody therapy, and chimeric antigen receptor/T-cell receptor - T-cell therapy and discuss additional strategies for effectively eliminating HCC through immunotherapy.GPC3 is an ideal cancer antigen for HCC immunotherapy. In resectable HCC, immunotherapies that leverage physiological immune surveillance, immune checkpoint inhibitors, and GPC3-target cancer vaccines appear promising in preventing recurrence and could be considered as a prophylactic adjuvant therapy. However, in advanced HCC, clinical trials have not demonstrated sufficient anti-tumor efficacy, in contrast with preclinical studies. Reverse translation, bedside-to-bench research, is crucial to identify the factors that have hindered GPC3 target immunotherapies.