文章：

利用基于载体的基因敲除技术增强CAR T细胞疗效

Leveraging Vector-Based Gene Disruptions to Enhance CAR T-Cell Effectiveness

原文发布日期：24 January 2025

DOI: 10.3390/cancers17030383

类型: Article

开放获取: 是

英文摘要：

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough in the treatment of relapsed and refractory B-cell malignancies, such as chronic lymphocytic leukemia (CLL), inducing long-term, sometimes curative, responses. However, fewer than 30% of CLL patients achieve such outcomes. It has been shown that a smaller subset of T cells capable of expansion and persistence is crucial for treatment effectiveness. Notably, a pre-existing mutation in the epigenetic regulator TET2, combined with CAR vector-induced disruption of the other intact allele, significantly enhanced the potency of the CAR-engineered T-cell clone in one CLL patient. This finding aligns with independent research, suggesting that the CAR gene’s genomic insertion site influences tumor-targeting capability. Thus, it is plausible that vector-induced gene disruptions affect CAR T-cell function. This review synthesizes existing knowledge on vector integration into the host genome and its impact on clinical outcomes in CAR T-cell therapy patients. Our aim is to inform the development of improved therapies and enhance their overall efficacy.

摘要翻译： 

抗CD19嵌合抗原受体（CAR）T细胞疗法是治疗复发难治性B细胞恶性肿瘤（如慢性淋巴细胞白血病）的一项突破性进展，能够诱导长期甚至治愈性疗效。然而，仅有不足30%的慢性淋巴细胞白血病患者能达到此类治疗效果。研究表明，具有扩增和持久存活能力的T细胞亚群对治疗有效性至关重要。值得注意的是，在一例慢性淋巴细胞白血病患者中，表观遗传调控因子TET2的既存突变与CAR载体诱导的另一完整等位基因破坏相结合，显著增强了CAR工程化T细胞克隆的效力。这一发现与独立研究结果相吻合，表明CAR基因的基因组插入位点会影响其靶向肿瘤的能力。因此，载体诱导的基因破坏可能影响CAR T细胞功能。本综述整合了关于载体整合至宿主基因组及其对CAR T细胞疗法患者临床结局影响的现有认知，旨在为优化治疗方案、提升整体疗效提供理论依据。

原文链接：

Leveraging Vector-Based Gene Disruptions to Enhance CAR T-Cell Effectiveness