Acute myeloid leukemia (AML) is an aggressive disease with poor outcomes, overwhelmingly due to relapse. Minimal residual disease (MRD), defined as the persistence of leukemic cells after chemotherapy treatment, is thought to be the major cause of relapse. The origins of relapse in AML have been traced to rare therapy-resistant leukemic stem cells (LSCs) that are already present at diagnosis. Effective treatment strategies for long-term remission are lacking, as it has been difficult to eliminate LSCs with conventional therapy. Here, we proposed a new approach based on the chimeric antigen receptor (CAR)-directed T lymphocytes, targeting T-cell immunoglobulin, and mucin domain 3 (TIM-3) to treat MRD in patients with AML. TIM-3 is selected as the target because it is highly expressed on AML blasts and LSCs in most subtypes regardless of the patient's genetic characteristics and treatment course. Moreover, it is absent in the normal hematopoietic stem cells, granulocytes, naïve lymphocytes, and most normal nonhematopoietic tissues. Using a naïve human Fab phage display library, we isolated an anti-human TIM-3 antibody and designed a second-generation anti–TIM-3. Our anti–TIM-3 CAR T cells exhibit potent antileukemic activity against AML cell lines and primary AML blasts, and in the mouse models. More importantly, we demonstrate efficient killing of the primary LSCs directly isolated from the patients. Hence, eradication of the LSCs present in the MRD by anti–TIM-3 CAR T-cell therapy following the first-line treatment may improve the clinical outcomes of patients with AML. This article is featured in Highlights of This Issue, [p. 1497][1] [1]: /lookup/volpage/20/1497?iss=9

中文翻译：

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TIM-3靶向嵌合抗原受体T细胞有效杀伤急性髓系白血病

急性髓性白血病 (AML) 是一种预后不良的侵袭性疾病，绝大多数是由于复发。微小残留病（MRD），定义为化疗后白血病细胞的持续存在，被认为是复发的主要原因。AML 复发的起源可追溯到诊断时已经存在的罕见的抗治疗白血病干细胞 (LSC)。缺乏长期缓解的有效治疗策略，因为传统治疗难以消除 LSC。在这里，我们提出了一种基于嵌合抗原受体 (CAR) 导向的 T 淋巴细胞、靶向 T 细胞免疫球蛋白和粘蛋白结构域 3 (TIM-3) 的新方法来治疗 AML 患者的 MRD。选择 TIM-3 作为靶点是因为它在大多数亚型的 AML 原始细胞和 LSC 上高度表达，无论患者的遗传特征和治疗过程如何。此外，它在正常造血干细胞、粒细胞、幼稚淋巴细胞和大多数正常非造血组织中不存在。使用初始人类 Fab 噬菌体展示文库，我们分离了抗人类 TIM-3 抗体并设计了第二代抗 TIM-3。我们的抗 TIM-3 CAR T 细胞对 AML 细胞系和原发性 AML 原始细胞以及在小鼠模型中表现出有效的抗白血病活性。更重要的是，我们展示了直接从患者中分离出来的原发性 LSC 的有效杀灭。因此，在一线治疗后通过抗 TIM-3 CAR T 细胞疗法根除 MRD 中存在的 LSC 可能会改善 AML 患者的临床结果。这篇文章被收录在本期的亮点中，[p. 1497][1][1]：/lookup/volpage/20/1497?iss=9