研究动态
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急性髓系白血病的免疫治疗:临床观点。

The Immunotherapy of Acute Myeloid Leukemia: A Clinical Point of View.

发表日期:2024 Jun 27
作者: Federico Mosna
来源: CYTOKINE & GROWTH FACTOR REVIEWS

摘要:

同种异体造血干细胞移植后和供体白细胞输注背景下发生的移植物抗白血病效应一致证明了免疫系统消灭白血病细胞的潜力。因此,目前正在测试各种免疫治疗方法,包括使用抗体、抗体-药物缀合物、双特异性 T 细胞接合剂、嵌合抗原受体 (CAR) T 细胞和 NK 细胞的治疗性输注,这些方法有希望但相互矛盾。结果。本综述将从临床血液学家的角度重点关注临床前和临床开发中的各种类型的免疫疗法。最有前途的临床转化疗法是使用针对谱系限制性抗原的双特异性 T 细胞接合剂和 CAR-T 细胞,在一小批经过严格预处理的药物中可以实现 20% 至 40% 的总体反应 (ORR)患有难治性或复发性白血病的患者。毒性主要在于细胞因子释放综合征的发生,这通常可以通过逐步给药、早期使用细胞因子阻断剂和皮质类固醇以及骨髓抑制来控制。各种细胞因子增强的自然杀伤产品也正在接受测试,主要作为同种异体现成疗法,具有良好的耐受性和有希望的结果(ORR:小型试验中的 20-37.5%)。通过抑制免疫检查点来体内激活 T 淋巴细胞和 NK 细胞也产生了有趣但有限的结果(ORR:33-59%),但移植患者发生严重移植物抗宿主病的风险增加。因此,在这些新型化合物广泛应用于临床之前,仍有几个障碍需要克服。
The potential of the immune system to eradicate leukemic cells has been consistently demonstrated by the Graft vs. Leukemia effect occurring after allo-HSCT and in the context of donor leukocyte infusions. Various immunotherapeutic approaches, ranging from the use of antibodies, antibody-drug conjugates, bispecific T-cell engagers, chimeric antigen receptor (CAR) T-cells, and therapeutic infusions of NK cells, are thus currently being tested with promising, yet conflicting, results. This review will concentrate on various types of immunotherapies in preclinical and clinical development, from the point of view of a clinical hematologist. The most promising therapies for clinical translation are the use of bispecific T-cell engagers and CAR-T cells aimed at lineage-restricted antigens, where overall responses (ORR) ranging from 20 to 40% can be achieved in a small series of heavily pretreated patients affected by refractory or relapsing leukemia. Toxicity consists mainly in the occurrence of cytokine-release syndrome, which is mostly manageable with step-up dosing, the early use of cytokine-blocking agents and corticosteroids, and myelosuppression. Various cytokine-enhanced natural killer products are also being tested, mainly as allogeneic off-the-shelf therapies, with a good tolerability profile and promising results (ORR: 20-37.5% in small trials). The in vivo activation of T lymphocytes and NK cells via the inhibition of their immune checkpoints also yielded interesting, yet limited, results (ORR: 33-59%) but with an increased risk of severe Graft vs. Host disease in transplanted patients. Therefore, there are still several hurdles to overcome before the widespread clinical use of these novel compounds.