肿瘤细胞治疗研究
英文原题：Chimeric antigen receptor (CAR) modified T Cells in acute myeloid leukemia: limitations and expectations.
急性髓系白血病（AML）是一种侵袭性血液肿瘤，尽管新型疗法不断出现，预后仍然不佳。
急性髓系白血病（AML）是一种侵袭性血液系统恶性肿瘤，即使新型疗法不断出现，预后仍较差。因此，尤其对复发/难治性（R/R）AML 患者而言，存在重大未满足的新治疗需求。近年来，随着多种靶向疗法出现，部分患者的治疗已可个体化；但仍有相当多患者缺乏治疗选择，且疾病复发率高使总体预后不佳。相比之下，细胞疗法，尤其是嵌合抗原受体（CAR）T 细胞疗法，已显著改变弥漫性大 B 细胞淋巴瘤和急性淋巴细胞白血病等血液肿瘤的治疗选择。但有效使用 CAR 免疫疗法治疗 AML 面临重大的生物学和临床挑战，主要是尚未找到仅在 AML 原始细胞表达、又不损害正常造血干细胞存活的合适靶抗原。尽管这些局限阻碍了 CAR-T 的临床转化，多项临床试验已使用 CD123、CLL-1 或 CD33 等靶抗原治疗 AML，初步结果令人鼓舞。研究者也持续努力提高 AML CAR-T 的特异性和疗效，包括开发双 CAR-T 和下一代 CAR-T，并利用基因编辑工具降低瘤外毒性。本综述总结 AML CAR-T 正在开展的临床研究及早期临床结果，指出其局限和最新克服策略，并讨论 CAR-T 在 AML 治疗中的适用时机和方式。
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis despite the advent of novel therapies. Consequently, a major need exists for new therapeutic options, particularly for patients with relapsed/refractory (R/R) AML. In recent years, it has been possible to individualize the treatment of a subgroup of patients, particularly with the emergence of multiple targeted therapies. Nonetheless, a considerable number of patients remain without therapeutic options, and overall prognosis remains poor because of a high rate of disease relapse. In this sense, cellular therapies, especially chimeric antigen receptor (CAR)-T cell therapy, have dramatically shifted the therapeutic options for other hematologic malignancies, such as diffuse large B cell lymphoma and acute lymphoblastic leukemia. In contrast, effectively treating AML with CAR-based immunotherapy poses major biological and clinical challenges, most of them derived from the unmet need to identify target antigens with expression restricted to the AML blast without compromising the viability of the normal hematopoietic stem cell counterpart. Although those limitations have hampered CAR-T cell therapy translation to the clinic, there are several clinical trials where target antigens, such as CD123, CLL-1 or CD33 are being used to treat AML patients showing promising results. Moreover, there are continuing efforts to enhance the specificity and efficacy of CAR-T cell therapy in AML. These endeavors encompass the exploration of novel avenues, including the development of dual CAR-T cells and next-generation CAR-T cells, as well as the utilization of gene editing tools to mitigate off-tumor toxicities. In this review, we will summarize the ongoing clinical studies and the early clinical results reported with CAR-T cells in AML, as well as highlight CAR-T cell limitations and the most recent approaches to overcome these barriers. We will also discuss how and when CAR-T cells should be used in the context of AML.
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