The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma

被引:453
作者
Mahoney, Kathleen M. [1 ,2 ]
Freeman, Gordon J. [2 ]
McDermott, David F. [1 ]
机构
[1] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Hematol & Oncol, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
melanoma; MPDL3280A; nivolumab; PD-1; PD-L1; pembrolizumab; pidilizumab; programmed cell death 1; T-CELL-ACTIVATION; REGULATORY T; ANTI-PD-L1; ANTIBODY; INDUCED EXPRESSION; CARCINOMA PATIENTS; CLINICAL ACTIVITY; TUMOR-CELLS; PHASE-I; PD-1; SAFETY;
D O I
10.1016/j.clinthera.2015.02.018
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Purpose: 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. Methods: Pub Med 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. Findings: 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. Implications: 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. (Clin Ther. 2015;37:764-782) (C) 2015 Elsevier HS Journals, Inc. All rights reserved.
引用
收藏
页码:764 / 782
页数:19
相关论文
共 89 条
[1]  
Adjei AA, 2013, J CLIN ONCOL, V31
[2]   The butyrophilin (BTN) gene family: from milk fat to the regulation of the immune response [J].
Afrache, Hassnae ;
Gouret, Philippe ;
Ainouche, Shanaiz ;
Pontarotti, Pierre ;
Olive, Daniel .
IMMUNOGENETICS, 2012, 64 (11) :781-794
[3]  
Alegre ML, 1996, J IMMUNOL, V157, P4762
[4]  
[Anonymous], J CLIN ONCOL S
[5]  
[Anonymous], J CLIN ONCOL S
[6]  
[Anonymous], J CLIN ONCOL S
[7]   Disabling Immune Tolerance by Programmed Death-1 Blockade With Pidilizumab After Autologous Hematopoietic Stem-Cell Transplantation for Diffuse Large B-Cell Lymphoma: Results of an International Phase II Trial [J].
Armand, Philippe ;
Nagler, Arnon ;
Weller, Edie A. ;
Devine, Steven M. ;
Avigan, David E. ;
Chen, Yi-Bin ;
Kaminski, Mark S. ;
Holland, H. Kent ;
Winter, Jane N. ;
Mason, James R. ;
Fay, Joseph W. ;
Rizzieri, David A. ;
Hosing, Chitra M. ;
Ball, Edward D. ;
Uberti, Joseph P. ;
Lazarus, Hillard M. ;
Mapara, Markus Y. ;
Gregory, Stephanie A. ;
Timmerman, John M. ;
Andorsky, David ;
Or, Reuven ;
Waller, Edmund K. ;
Rotem-Yehudar, Rinat ;
Gordon, Leo I. .
JOURNAL OF CLINICAL ONCOLOGY, 2013, 31 (33) :4199-4206
[8]  
ATKINS MB, 2014, J CLIN ONCOL S, V32
[9]   Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies [J].
Berger, Raanan ;
Rotem-Yehudar, Rinat ;
Slama, Gideon ;
Landes, Shimon ;
Kneller, Abraham ;
Leiba, Merav ;
Koren-Michowitz, Maya ;
Shimoni, Avichai ;
Nagler, Arnon .
CLINICAL CANCER RESEARCH, 2008, 14 (10) :3044-3051
[10]   Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer [J].
Brahmer, Julie R. ;
Tykodi, Scott S. ;
Chow, Laura Q. M. ;
Hwu, Wen-Jen ;
Topalian, Suzanne L. ;
Hwu, Patrick ;
Drake, Charles G. ;
Camacho, Luis H. ;
Kauh, John ;
Odunsi, Kunle ;
Pitot, Henry C. ;
Hamid, Omid ;
Bhatia, Shailender ;
Martins, Renato ;
Eaton, Keith ;
Chen, Shuming ;
Salay, Theresa M. ;
Alaparthy, Suresh ;
Grosso, Joseph F. ;
Korman, Alan J. ;
Parker, Susan M. ;
Agrawal, Shruti ;
Goldberg, Stacie M. ;
Pardoll, Drew M. ;
Gupta, Ashok ;
Wigginton, Jon M. .
NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (26) :2455-2465