Oliveira Beatriz C, Bari Saaurav, Melenhorst J Joseph
Cell Therapy & Immuno-Engineering Program, Center for Immunotherapy and Precision Immuno-Oncology, Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44016, USA.
Cancers (Basel). 2025 Jan 24;17(3):383. doi: 10.3390/cancers17030383.
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.
抗CD19嵌合抗原受体（CAR）T细胞疗法是复发和难治性B细胞恶性肿瘤（如慢性淋巴细胞白血病（CLL））治疗领域的一项突破，可诱导长期、有时甚至是治愈性的反应。然而，只有不到30%的CLL患者能达到这样的治疗效果。研究表明，一小部分能够扩增和持续存在的T细胞对治疗效果至关重要。值得注意的是，表观遗传调节因子TET2的一个预先存在的突变，加上CAR载体诱导的另一个完整等位基因的破坏，在一名CLL患者中显著增强了CAR工程化T细胞克隆的效力。这一发现与独立研究结果一致，表明CAR基因的基因组插入位点会影响肿瘤靶向能力。因此，载体诱导的基因破坏影响CAR T细胞功能是有道理的。这篇综述综合了关于载体整合到宿主基因组及其对CAR T细胞治疗患者临床结果影响的现有知识。我们的目的是为改进疗法的开发提供信息并提高其总体疗效。
