The emerging role of immune checkpoint based approaches in AML and MDS.
The emerging role of immune checkpoint based approaches in AML and MDS.
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DOI：
10.1080/10428194.2017.1344905
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发表时间：
2018-04
影响因子：
2.6
通讯作者：
Daver N
中科院分区：
文献类型：
--
作者：
Boddu P;Kantarjian H;Garcia-Manero G;Allison J;Sharma P;Daver N
免疫检查点抑制剂的开发代表了癌症治疗领域的重大突破。鉴于它们在黑色素瘤和多种实体瘤恶性肿瘤中取得的成功，这些药物正在针对血液恶性肿瘤进行研究，包括急性髓性白血病 (AML) 和骨髓增生异常综合征 (MDS)。尽管传统上认为 AML/MDS 的免疫原性低于实体瘤恶性肿瘤，但最近的临床前模型表明免疫检查点抑制在这些疾病中具有治疗作用。 CTLA-4 抑制对于治疗患有有限或无移植物抗宿主病的患者的 AML 晚期异基因干细胞移植后复发可能特别有效。免疫检查点抑制，特别是 PD-1 抑制，在复发性 AML 和 MDS 低甲基化治疗后的患者中显示单药疗效有限。需要合理设计的 PD-1 抑制剂与标准抗白血病治疗的组合。阿扎胞苷等去甲基化药物可上调 AML/MDS 患者的 PD-1、PD-L1 和 PD-L2，并且这些基因的上调与耐药性的出现相关。阿扎胞苷和 PD-1/PD-L1 抑制的组合可能是预防或克服 5-阿扎胞苷耐药性的潜在机制。许多此类组合正在临床试验中进行评估，并取得了令人鼓舞的早期结果。免疫检查点抑制也是一种有吸引力的选择，可通过加强高危 AML 患者的 T 细胞监测来提高无复发生存率或消除诱导和巩固后的微小残留病。正在进行的检查点抑制剂治疗 AML/MDS 的临床试验将提高我们对这些疾病的免疫生物学的理解，并指导我们在 AML/MDS 治疗中最合适地应用这些药物。
The development of immune checkpoint inhibitors represents a major breakthrough in the field of cancer therapeutics. Pursuant to their success in melanoma and numerous solid tumor malignancies, these agents are being investigated in hematological malignancies including acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Although AML/MDS have traditionally been considered to be less immunogenic than solid tumor malignancies, recent pre-clinical models suggest a therapeutic role for immune checkpoint inhibition in these diseases. CTLA-4 inhibition may be especially effective in treating late post-allogeneic stem cell transplant relapse of AML in patients with limited or no graft versus host disease. Immune checkpoint inhibition, specifically PD-1 inhibition, demonstrated limited single agent efficacy in patients with relapsed AML and with MDS post-hypomethylating therapy. Rationally designed combinations of PD-1 inhibitors with standard anti-leukemic therapy are needed. Hypomethylating agents such as azacitidine, up-regulate PD-1, PD-L1, and PD-L2 in patients with AML/MDS and up-regulation of these genes was associated with the emergence of resistance. The combination of azacitidine and PD-1/PD-L1 inhibition may be a potential mechanism to prevent or overcome resistance to 5-azacitidine. A number of such combinations are being evaluated in clinical trials with early encouraging results. Immune checkpoint inhibition is also an attractive option to improve relapse-free survival or eliminate minimal residual disease post induction and consolidation by enhancing T-cell surveillance in patients with high-risk AML. The ongoing clinical trials with checkpoint inhibitors in AML/MDS will improve our understanding of the immunobiology of these diseases and guide us to the most appropriate application of these agents in the therapy of AML/MDS.
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DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
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作者：
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作者：
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作者：
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影响因子：
11.5
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