The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma.
The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma.
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DOI：
10.1016/j.clinthera.2015.02.018
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发表时间：
2015-04-01
影响因子：
3.2
通讯作者：
McDermott DF
中科院分区：
文献类型：
--
作者：
Mahoney KM;Freeman GJ;McDermott DF
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令人印象深刻的抗肿瘤反应。针对这一途径的治疗方法目前正在临床试验中。Pembrolizumab和nivolumab是首个获得美国食品和药物管理局（FDA）加速批准用于治疗伊匹单抗难治性黑色素瘤的抗pd -1途径检查点抑制剂家族。与达卡巴嗪相比，Nivolumab与先前未经治疗的野生型丝氨酸/苏氨酸蛋白激酶B-raf原癌基因BRAF黑色素瘤患者的总生存率提高有关。尽管最成熟的数据是在黑色素瘤的治疗中，FDA已经批准了nivolumab用于鳞状细胞肺癌的治疗，以及用于其他癌症的免疫检查点抑制剂的突破性治疗指定：nivolumab是一种抗pd -1单克隆抗体，用于霍奇金淋巴瘤，MPDL-3280A是一种抗pd - l1单克隆抗体，用于膀胱癌和非小细胞肺癌。在这里，我们回顾了PD-1和PD-L1阻断的文献，并重点关注已报道的包括黑色素瘤患者的临床研究。检索PubMed以确定PD-1/ pd - l1靶向治疗黑色素瘤的相关临床研究。鉴于已发表的关于该主题的临床试验数量有限，我们纳入了clinicaltrial.gov网站上当前试验数据的回顾，以及2014年美国临床肿瘤学会年会摘要中提供的数据。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令人印象深刻的抗肿瘤作用。在未选择的患者中，最大的临床活动见于黑色素瘤。肿瘤中PD-L1的表达是一种提示性的，但不充分的，预测免疫检查点阻断反应的生物标志物。然而，表达少量或不表达PD-L1的肿瘤对PD-1通路阻断的反应较小。检查点阻断联合PD-1 +细胞毒性t淋巴细胞抗原(CTLA)-4阻断似乎可以提高对单检查点阻断不太可能应答的患者的应答率。PD-1阻滞剂的毒性小于以前的免疫疗法（如白细胞介素2、CTLA-4阻断剂）的毒性。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，大多数不良事件是可以预防或逆转的。这个免疫检查点抑制剂家族不仅有利于转移性黑色素瘤患者，也有利于那些历史上反应性较低的肿瘤类型。虽然一小部分患者对单药阻断有反应，但检查点抑制剂联合治疗的初步试验报告了提高反应率的潜力。联合治疗似乎是提高反应率的一种手段，尽管与免疫相关的不良事件增加。随着这些治疗方法对患者可用，关于识别和管理免疫检查点封锁的免疫相关影响的教育对于最大化临床效益至关重要。
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.
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影响因子：
20.3
作者：
Green, Michael R.;Monti, Stefano;Shipp, Margaret A.
通讯作者：
Shipp, Margaret A.
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM
影响因子：
64.8
作者：
Herbst RS;Soria JC;Kowanetz M;Fine GD;Hamid O;Gordon MS;Sosman JA;McDermott DF;Powderly JD;Gettinger SN;Kohrt HE;Horn L;Lawrence DP;Rost S;Leabman M;Xiao Y;Mokatrin A;Koeppen H;Hegde PS;Mellman I;Chen DS;Hodi FS
通讯作者：
Hodi FS
影响因子：
11.5
作者：
Berger, Raanan;Rotem-Yehudar, Rinat;Nagler, Arnon
通讯作者：
Nagler, Arnon
影响因子：
64.8
作者：
Day, Cheryl L.;Kaufmann, Daniel E.;Walker, Bruce D.
通讯作者：
Walker, Bruce D.