解锁T细胞耗竭：机制洞察及对CAR-T细胞治疗的启示
Unlocking T cell exhaustion: Insights and implications for CAR-T cell therapy
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影响因子:14.6
分区:医学1区 Top / 药学1区
发表日期:2024 Aug
作者:
Dian Xiong, Haijun Yu, Zhi-Jun Sun
DOI:
10.1016/j.apsb.2024.04.022
摘要
嵌合抗原受体T细胞（CAR-T）疗法作为一种过继细胞治疗（ACT），在癌症治疗中展现出巨大潜力，已获FDA批准的针对CD19或B细胞成熟抗原（BCMA）的血液系统恶性肿瘤CAR-T疗法，尽管在实体瘤中的效果尚属中等。然而，尽管取得了这些进展，CAR-T疗法的有效性常受到T细胞耗竭的影响，T细胞耗竭阻碍了CAR-T细胞的持续存在和效应功能，导致接受CD19或CD22 CAR-T治疗的血液恶性肿瘤患者的复发率高达75%。为克服CAR-T耗竭，采用了最先进的基因工程工具和单细胞测序技术。在本文综述中，我们提供了关于T细胞耗竭最新机制洞察的全面理解及其对优化CAR-T细胞疗法的意义。这些见解结合近期临床试验中基于CAR-T的产品的经验教训，旨在解决T细胞耗竭带来的挑战，并为开发个性化下一代癌症治疗策略奠定基础。
Abstract
Chimeric antigen receptor T (CAR-T) cell therapy as a form of adoptive cell therapy (ACT) has shown significant promise in cancer treatment, demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen (BCMA) for hematological malignancies, albeit with moderate outcomes in solid tumors. However, despite these advancements, the efficacy of CAR-T therapy is often compromised by T cell exhaustion, a phenomenon that impedes the persistence and effector function of CAR-T cells, leading to a relapse rate of up to 75% in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies. Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies. In this review, we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy. These insights, combined with lessons learned from benchmarking CAR-T based products in recent clinical trials, aim to address the challenges posed by T cell exhaustion, potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.