Abstract：
Despite several small-molecule drugs that have revolutionized the current treatment strategy for acute myeloid leukemia (AML), hematopoietic stem cell transplantation remains the only curative treatment in most cases to date. Chimeric antigen receptor (CAR)-T cell therapy is one of the most promising next-generation cancer therapies for hematological malignancies and is clinically available for treatment of AML. However, developing AML-targeted CAR-T therapy is challenging because of the heterogeneity of target antigen expression across leukemic cells and patients, the difficulty in excluding on-/off-target tumor effects, and the immunosuppressive tumor microenvironment. To date, various targets, including CD33, NKG2D, CD123, CLL-1, and CD7, have been actively studied for CAR-T cells. Although no CAR-T cell products are close to practical use, several clinical trials have shown promising results, particularly for CAR-T cells targeting CLL-1 or CD123. Meanwhile, research exploring the ideal target for AML-targeted CAR-T therapy continues. Furthermore, as collecting autologous lymphocytes from patients with AML is difficult, development of off-the-shelf CAR-T products is being actively pursued. This review discusses the challenges in AML-targeted CAR-T cell therapy development from the perspectives of target antigen characteristics and AML-specific on-target/off-tumor toxicity. Moreover, it discusses the clinical development and prospects of AML-targeting CAR-T cells.
摘要：
尽管有几种小分子药物彻底改变了当前急性髓细胞性白血病（AML）的治疗策略，迄今为止，造血干细胞移植仍然是大多数情况下唯一的治愈性治疗方法。嵌合抗原受体(CAR)-T细胞疗法是用于血液恶性肿瘤的最有前途的下一代癌症疗法之一,并且临床上可用于治疗AML。然而,开发AML靶向CAR-T疗法具有挑战性，因为目标抗原表达在白血病细胞和患者之间存在异质性，难以排除靶点/脱靶肿瘤效应，和免疫抑制肿瘤微环境。迄今为止,各种目标,包括CD33，NKG2D，CD123、CLL-1和CD7已被积极研究用于CAR-T细胞。虽然没有CAR-T细胞产品接近实际使用，几项临床试验显示了有希望的结果，特别是针对靶向CLL-1或CD123的CAR-T细胞。同时,探索AML靶向CAR-T治疗理想靶点的研究仍在继续.此外，因为从AML患者中收集自体淋巴细胞是困难的，现货供应CAR-T产品的开发正在积极进行。本文从靶抗原特征和AML特异性上/外肿瘤毒性的角度讨论了AML靶向CAR-T细胞治疗发展中的挑战。此外，讨论了AML靶向CAR-T细胞的临床发展和前景。
