Jelinek Tomas, Mihalyova Jana, Kascak Michal, Duras Juraj, Hajek Roman
Department of Haemato-oncology, University Hospital Ostrava, Ostrava, Czech Republic.
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
Immunology. 2017 Nov;152(3):357-371. doi: 10.1111/imm.12788. Epub 2017 Aug 4.
The introduction of PD-1/PD-L1 pathway inhibitors is an important landmark in solid oncology with unprecedented practice-changing activity in various types of solid tumours. Among haematological malignancies, PD-1/PD-L1 inhibitors have been successful, so far, only in the treatment of classical Hodgkin lymphoma, which typically exhibits an over-expression of PD-1 ligands (PD-L1, PD-L2) due to alterations in chromosome 9p24.1. Such positive outcomes led to the US Food and Drug Administration approval of nivolumab use in relapsed Hodgkin lymphoma in 2016 as the first haematological indication. Although the results in other lymphoid malignancies have not been so striking, blockade of the PD-1/PD-L1 axis has led to meaningful responses in other lymphoma types such as diffuse large B-cell lymphoma, follicular lymphoma or several T-cell lymphomas. Monotherapy with PD-1/PD-L1 inhibitors in chronic lymphocytic leukaemia and multiple myeloma has been unsatisfactory, suggesting that a combinational approach with other synergistic drugs is needed. In the case of multiple myeloma, immunomodulatory agents together with corticosteroids represent the most promising combinations. Among myeloid malignancies, the anti-PD-1 monoclonal antibodies are examined dominantly in acute myeloid leukaemia and myelodysplastic syndromes in combination with potentially synergistic hypomethylating drugs such as 5-azacitidine, resulting in promising outcomes that warrant further investigation. We have described all available clinical results of PD-1/PD-L1 inhibitors in haematological malignancies and discussed related toxicities, as well as highlighted crucial preclinical studies in this review.
PD-1/PD-L1通路抑制剂的引入是实体肿瘤学中的一个重要里程碑,在各类实体肿瘤中展现出前所未有的改变临床实践的活性。在血液系统恶性肿瘤中,到目前为止,PD-1/PD-L1抑制剂仅在经典型霍奇金淋巴瘤的治疗中取得成功,该肿瘤由于9p24.1染色体改变通常表现为PD-1配体(PD-L1、PD-L2)过表达。这些阳性结果促使美国食品药品监督管理局于2016年批准纳武单抗用于复发型霍奇金淋巴瘤,这是首个血液学适应证。尽管在其他淋巴系统恶性肿瘤中的结果并不那么显著,但阻断PD-1/PD-L1轴已在其他淋巴瘤类型如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或几种T细胞淋巴瘤中产生了有意义的反应。在慢性淋巴细胞白血病和多发性骨髓瘤中,PD-1/PD-L1抑制剂单药治疗效果不佳,提示需要与其他具有协同作用的药物联合应用。就多发性骨髓瘤而言,免疫调节剂与糖皮质激素联合是最有前景的组合。在髓系恶性肿瘤中,抗PD-1单克隆抗体主要在急性髓系白血病和骨髓增生异常综合征中与潜在具有协同作用的低甲基化药物如5-氮杂胞苷联合应用进行研究,结果令人鼓舞,值得进一步探究。我们在本综述中描述了PD-1/PD-L1抑制剂在血液系统恶性肿瘤中的所有现有临床结果,讨论了相关毒性,并突出了关键的临床前研究。