肿瘤细胞治疗研究
英文原题：Cytokine-mediated CAR T therapy resistance in AML.
我们的研究结果表明，自体CART制备在AML中是可行的，但治疗与高发生率的细胞因子释放综合征和相对较差的临床疗效相关。
急性髓系白血病（AML）是一种快速进展的恶性肿瘤，难治性疾病缺乏有效疗法。迄今为止，嵌合抗原受体（CAR）T细胞疗法在AML中尚未重现其在B细胞恶性肿瘤中所见的疗效。在此，我们报告了一项在12名复发或难治性AML成人患者中进行的自体抗CD123 CAR T细胞的初步研究。靶向CD123+细胞的CAR T细胞在90.4%的生产运行中成功制备。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）。三名个体获得临床缓解（25%，90%置信区间0.07-0.53）。我们发现，髓系支持性细胞因子在细胞治疗期间被分泌，并通过激酶信号支持AML原始细胞存活，导致CAR T细胞耗竭。治疗诱导的细胞因子的促存活效应呈现了一种AML中独特的耐药机制，不同于在B细胞恶性肿瘤中观察到的任何机制。我们的发现表明，自体CAR T制备在AML中是可行的，但治疗与高发生率的细胞因子释放综合征和相对较差的临床疗效相关。将CAR T细胞疗法与细胞因子信号抑制剂联合可能增强AML中的免疫治疗疗效并实现改善的结局（ClinicalTrials.gov标识符：NCT03766126）。
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 ).
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