Mahoney Kathleen M, Freeman Gordon J, McDermott David F
Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts.
Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts.
Clin Ther. 2015 Apr 1;37(4):764-82. doi: 10.1016/j.clinthera.2015.02.018. Epub 2015 Mar 29.
Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma.
PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.
The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management.
This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.
据报道，阻断程序性细胞死亡（PD）-1蛋白与其配体之一PD-L1之间的相互作用具有显著的抗肿瘤反应。靶向该途径的治疗方法目前正在进行临床试验。派姆单抗和纳武单抗是抗PD-1途径的检查点抑制剂家族中首批获得美国食品药品监督管理局（FDA）加速批准用于治疗伊匹单抗难治性黑色素瘤的药物。在先前未治疗的野生型丝氨酸/苏氨酸蛋白激酶B-raf原癌基因BRAF黑色素瘤患者中，与达卡巴嗪相比，纳武单抗与总生存期的改善相关。尽管最成熟的数据是在黑色素瘤治疗方面，但FDA已批准纳武单抗用于治疗鳞状细胞肺癌，并授予免疫检查点抑制剂用于其他癌症的突破性治疗指定：抗PD-1单克隆抗体纳武单抗用于霍奇金淋巴瘤，抗PD-L1单克隆抗体MPDL-3280A用于膀胱癌和非小细胞肺癌。在此，我们回顾关于PD-1和PD-L1阻断的文献，并重点关注纳入黑色素瘤患者的已报道临床研究。
检索PubMed以确定黑色素瘤中针对PD-1/PD-L1靶向治疗的相关临床研究。纳入了对clinicaltrial.gov上当前试验数据的综述，以及在2014年美国临床肿瘤学会年会上摘要中呈现的数据，因为关于该主题已发表的临床试验数量有限。
据报道，抗PD-1和抗PD-L1药物在包括黑色素瘤在内的几种恶性肿瘤中具有显著的抗肿瘤作用。在未选择的患者中，最大的临床活性见于黑色素瘤。PD-L1的肿瘤表达是预测免疫检查点阻断反应的一个提示性但不充分的生物标志物。然而，表达很少或不表达PD-L1的肿瘤对PD-1途径阻断反应的可能性较小。将检查点阻断与PD-1加细胞毒性T淋巴细胞抗原（CTLA）-4阻断联合使用似乎可提高对单检查点阻断反应可能性较小的患者的反应率。与先前的免疫疗法（如白细胞介素2、CTLA-4阻断）相比，PD-1阻断剂的毒性较小。某些不良事件可能很严重并可能危及生命，但通过密切监测和适当管理，大多数可以预防或逆转。
这一免疫检查点抑制剂家族不仅使转移性黑色素瘤患者受益，也使那些历史上反应较差的肿瘤类型患者受益。尽管一部分患者对单药阻断有反应，但检查点抑制剂联合使用的初步试验已报道有提高反应率的潜力。联合疗法似乎是提高反应率的一种手段，尽管免疫相关不良事件有所增加。随着这些治疗方法可供患者使用，关于免疫检查点阻断的免疫相关效应的识别和管理的教育对于最大化临床益处至关重要。
