Journal Article

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

Hu-Lieskovan, Siwen, Schumacher, Ton N.M, Berent-Maoz, Beata, Saco, Justin, Graeber, Thomas G, Pang, Jia, Puig-Saus, Cristina, Ribas, Antoni, Garcia-Diaz, Angel, Escuin-Ordinas, Helena, Sanchez, Phillip J, Homet Moreno, Blanca, Comin-Anduix, Begoña, Cherry, Grace, Kong, Xiangju, Torrejon, Davis Y, Abril-Rodriguez, Gabriel, Sandoval, Salemiz, Barthly, Lucas, Seja, Elizabeth, Hugo, Willy, Shin, Daniel S, Tumeh, Paul C, Ruchalski, Kathleen, Mezzadra, Riccardo, Chmielowski, Bartosz, Zaretsky, Jesse M, Lo, Roger S, Shintaku, I. Peter

2016

Overview

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 . . .

• Publisher: Massachusetts Medical Society
• Subject: 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