Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

Whole-exome sequencing was performed on four patients' tumors before exposure to pembrolizumab and after disease progression following a response to treatment. Acquired mutations involving antigen presentation and interferon response were noted. Durable responses in metastatic cancers have been...

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Veröffentlicht in:The New England journal of medicine Jg. 375; H. 9; S. 819 - 829
Hauptverfasser: Zaretsky, Jesse M, Garcia-Diaz, Angel, Shin, Daniel S, Escuin-Ordinas, Helena, Hugo, Willy, Hu-Lieskovan, Siwen, Torrejon, Davis Y, Abril-Rodriguez, Gabriel, Sandoval, Salemiz, Barthly, Lucas, Saco, Justin, Homet Moreno, Blanca, Mezzadra, Riccardo, Chmielowski, Bartosz, Ruchalski, Kathleen, Shintaku, I. Peter, Sanchez, Phillip J, Puig-Saus, Cristina, Cherry, Grace, Seja, Elizabeth, Kong, Xiangju, Pang, Jia, Berent-Maoz, Beata, Comin-Anduix, Begoña, Graeber, Thomas G, Tumeh, Paul C, Schumacher, Ton N.M, Lo, Roger S, Ribas, Antoni
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Massachusetts Medical Society 01.09.2016
Schlagworte:
Antibodies, Monoclonal, Humanized - therapeutic use
Antigen presentation
Antigens
Antineoplastic Agents - therapeutic use
Apoptosis
beta 2-Microglobulin - genetics
Biopsy
Cancer
Clonal deletion
Clonal selection
Drug Resistance, Neoplasm - genetics
Exome
Gene deletion
Gene Expression Regulation, Neoplastic
Genes, MHC Class I
Humans
Immunotherapy
Interferon-gamma - therapeutic use
Janus kinase
Janus Kinase 1 - genetics
Janus kinase 2
Janus Kinase 2 - genetics
Major histocompatibility complex
Melanoma
Melanoma - drug therapy
Melanoma - genetics
Melanoma - secondary
Metastases
Metastasis
Monoclonal antibodies
Mutation
PD-1 protein
Pembrolizumab
Programmed Cell Death 1 Receptor - antagonists & inhibitors
Programmed Cell Death 1 Receptor - metabolism
Recurrence
Sequence Analysis, DNA
Signal Transduction
Targeted cancer therapy
Tumors
Los Angeles California
United States > US
ISSN:0028-4793, 1533-4406, 1533-4406
Online-Zugang:Volltext
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Zusammenfassung:Whole-exome sequencing was performed on four patients' tumors before exposure to pembrolizumab and after disease progression following a response to treatment. Acquired mutations involving antigen presentation and interferon response were noted. Durable responses in metastatic cancers have been achieved with a variety of immunotherapies such as interleukin-2, adoptive cell transfer of tumor-infiltrating lymphocytes, antibodies that block cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), 1 – 5 and antibodies that block programmed death 1 (PD-1). 6 – 10 However, in a recent study, approximately 25% of patients with melanoma who had had an objective response to PD-1 blockade therapy had disease progression at a median follow-up of 21 months. 11 The mechanisms of immune-resistant cancer progression are mostly unknown. Previous studies involving humans examined the loss of beta-2-microglobulin as a mechanism of acquired resistance to several forms of cancer . . .
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0028-4793
1533-4406
1533-4406
DOI:10.1056/NEJMoa1604958