急性髓系白血病（AML）是一种快速进展的恶性肿瘤，目前尚无有效的难治性疾病治疗方法。迄今为止，嵌合抗原受体 (CAR) T 细胞治疗 AML 尚未重现 B 细胞恶性肿瘤中的疗效。在此，我们报告了一项针对 12 名患有复发性或难治性 AML 成人的自体抗 CD123 CAR T 细胞的初步研究。靶向 CD123 细胞的 CAR T 细胞在 90.4% 的运行中成功制造。 12 名输注个体中有 10 名观察到细胞因子释放综合征（83.3%，90% 置信区间 0.5-0.97）。三人取得了临床缓解（25%，90% 置信区间 0.07-0.53）。我们发现，细胞治疗过程中会分泌支持骨髓的细胞因子，并通过激酶信号传导支持 AML 母细胞存活，从而导致 CAR T 细胞耗竭。治疗诱导的细胞因子的促生存作用在 AML 中呈现出独特的抵抗机制，与 B 细胞恶性肿瘤中观察到的任何机制都不同。我们的研究结果表明，自体 CART 制造在 AML 中是可行的，但治疗与细胞因子释放综合征的高发生率和相对较差的临床疗效有关。将 CAR T 细胞疗法与细胞因子信号传导抑制剂相结合可以增强 AML 的免疫疗法疗效并改善疗效（ClinicalTrials.gov 标识符：NCT03766126）。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

Acute myeloid leukemia (AML) is a rapidly progressive malignancy without effective therapies for refractory disease. So far, chimeric antigen receptor (CAR) T cell therapy in AML has not recapitulated the efficacy seen in B cell malignancies. Here we report a pilot study of autologous anti-CD123 CAR T cells in 12 adults with relapsed or refractory AML. CAR T cells targeting CD123+ cells were successfully manufactured in 90.4% of runs. Cytokine release syndrome was observed in 10 of 12 infused individuals (83.3%, 90% confidence interval 0.5-0.97). Three individuals achieved clinical response (25%, 90% confidence interval 0.07-0.53). We found that myeloid-supporting cytokines are secreted during cell therapy and support AML blast survival via kinase signaling, leading to CAR T cell exhaustion. The prosurvival effect of therapy-induced cytokines presents a unique resistance mechanism in AML that is distinct from any observed in B cell malignancies. Our findings suggest that autologous CART manufacturing is feasible in AML, but treatment is associated with high rates of cytokine release syndrome and relatively poor clinical efficacy. Combining CAR T cell therapies with cytokine signaling inhibitors could enhance immunotherapy efficacy in AML and achieve improved outcomes (ClinicalTrials.gov identifier: NCT03766126 ).© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.