MICA/MICB下调可改善复发或难治性急性髓性白血病或骨髓增生异常瘤患者NKG2DL CAR - t细胞的细胞持久性和临床活性

IF 13.4 1区 医学 Q1 HEMATOLOGY
Daniel Pollyea, Tessa Kerre, Dries Deeren, Yves Beguin, Tara L. Lin, David A. Sallman, Sebastien Anguille, William G. Blum, Anne Flament, Eytan Breman, Caroline Lonez
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引用次数: 0

摘要

NKG2D受体结合8个在多种恶性肿瘤中过表达的配体(NKG2DL),但在非肿瘤细胞中大部分不存在。NKG2DL嵌合抗原受体(CAR) t细胞(CYAD-01)在复发或难治性(r/r)急性髓性白血病(AML)或骨髓增生异常瘤(MDS)患者中的初步临床评估显示,反应的持久性较低,细胞持久性较短。启动了两项I期试验,以评估在类似的急性髓性白血病/MDS患者群体中,在单次CAR - t细胞输注之前淋巴细胞清除的效果。DEPLETHINK试验(NCT03466320)评估了CYAD-01,而cycle1试验(NCT04167696)评估了下一代NKG2DL CAR CYAD-02,其中两个主要的NKG2D配体MICA和B下调,以增加CAR - t细胞的持久性。17例和12例患者在DEPLETHINK和CYCLE-1试验中接受治疗,证实了这两种产品的良好耐受性,分别有25%和33.3%的患者报告了细胞因子释放综合征(CRS) 3级或4级。与CYAD-01(无客观反应)相比,CYAD-02具有更高的植入率和更高的临床活性(17%的客观反应率)。总之,我们的数据提供了原理证明,MICA/B的敲除可以增强CAR - t细胞的持久性和有效性,同时保持良好的安全性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Downregulation of MICA/MICB improves cell persistence and clinical activity of NKG2DL CAR T-cells in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic neoplasia

Downregulation of MICA/MICB improves cell persistence and clinical activity of NKG2DL CAR T-cells in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic neoplasia

The NKG2D receptor binds eight ligands (NKG2DL) overexpressed in a wide range of malignancies, but largely absent on non-neoplastic cells. Initial clinical evaluation of NKG2DL chimeric antigen receptor (CAR) T-cells (CYAD-01) in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) or myelodysplastic neoplasia (MDS) demonstrated low durability of responses and short cell persistence. Two Phase I trials were initiated to evaluate the effect of lymphodepletion prior to a single CAR T-cell infusion in a similar r/r AML/MDS patient population. The DEPLETHINK trial (NCT03466320) evaluated CYAD-01 while the CYCLE-1 trial (NCT04167696) evaluated a next-generation NKG2DL CAR, CYAD-02, where the two main NKG2D ligands MICA and B are downregulated, to increase CAR T-cell persistence. Seventeen and twelve patients were treated in the DEPLETHINK and CYCLE-1 trials, and confirmed the good tolerability of both products with cytokine release syndrome (CRS) grade 3 or 4 reported in 25% and 33.3% of patients, respectively. CYAD-02 presented an higher engraftment and an improved clinical activity (17% objective response rate) compared to CYAD-01 (no objective response). Altogether, our data provide proof of principle that knock-down of MICA/B can enhance CAR T-cell persistence and efficacy while maintaining a good safety profile.

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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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