PDF(Pubmed)
Abstract：
Chimeric antigen receptor (CAR) T-cell therapy has ushered in substantial advancements in the management of various B-cell malignancies. However, its integration into chronic lymphocytic leukemia (CLL) treatment has been challenging, attributed largely to the development of very effective chemo-free alternatives. Additionally, CAR T-cell responses in CLL have not been as high as in other B-cell lymphomas or leukemias. However, a critical void exists in therapeutic options for patients with high-risk diseases who are resistant to the current CLL therapies, underscoring the urgency for adoptive immunotherapies in these patients. The diminished CAR T-cell efficacy within CLL can be traced to factors such as compromised T-cell fitness due to persistent antigenic stimulation inherent to CLL. Resistance mechanisms encompass tumor-related factors like antigen escape, CAR T-cell-intrinsic factors like T-cell exhaustion, and a suppressive tumor microenvironment (TME). New strategies to combat CAR T-cell resistance include the concurrent administration of therapies that augment CAR T-cell endurance and function, as well as the engineering of novel CAR T-cells targeting different antigens. Moreover, the concept of \"armored\" CAR T-cells, armed with transgenic modulators to modify both CAR T-cell function and the tumor milieu, is gaining traction. Beyond this, the development of readily available, allogeneic CAR T-cells and natural killer (NK) cells presents a promising countermeasure to innate T-cell defects in CLL patients. In this review, we explore the role of CAR T-cell therapy in CLL, the intricate tapestry of resistance mechanisms, and the pioneering methods studied to overcome resistance.
摘要：
嵌合抗原受体（CAR）T细胞疗法在各种B细胞恶性肿瘤的管理方面取得了重大进展。然而,将其整合到慢性淋巴细胞白血病（CLL）治疗中一直具有挑战性，很大程度上归因于开发非常有效的无化学替代品。此外,CLL中的CART细胞反应不如其他B细胞淋巴瘤或白血病高。然而,对于对目前的CLL疗法有抵抗力的高风险疾病患者，治疗方案存在一个关键的空白，强调了对这些患者进行过继免疫治疗的紧迫性。CLL内降低的CART细胞功效可以追溯到诸如由于CLL固有的持续抗原刺激而导致的T细胞适应性受损的因素。耐药机制包括肿瘤相关因素，如抗原逃逸，CART细胞内在因素，如T细胞衰竭，和抑制性肿瘤微环境（TME）。对抗CAR-T细胞抗性的新策略包括同时施用增强CAR-T细胞耐力和功能的疗法。以及针对不同抗原的新型CAR-T细胞的工程。此外，“装甲”汽车T细胞的概念，用转基因调节剂来修饰CAR-T细胞功能和肿瘤环境，正在获得牵引力。除此之外,现成的发展，同种异体CART细胞和自然杀伤（NK）细胞为CLL患者的先天性T细胞缺陷提供了有希望的对策。在这次审查中,我们探讨了CAR-T细胞治疗在CLL中的作用，复杂的抗性机制挂毯，以及克服阻力的开创性方法。
