Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors.
Aged
Antineoplastic Agents, Immunological
/ adverse effects
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Drug-Related Side Effects and Adverse Reactions
/ diagnosis
Female
Follow-Up Studies
Genetic Variation
HLA-DQ beta-Chains
/ genetics
Humans
Lung Neoplasms
/ drug therapy
Male
Melanoma
/ drug therapy
Middle Aged
Prognosis
Prospective Studies
Cancer immunotherapy
Human leukocyte antigen
Immune-related adverse events
Melanoma
Non–small cell lung cancer
Therapeutic marker
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
22
08
2018
accepted:
01
11
2018
pubmed:
12
12
2018
medline:
6
5
2020
entrez:
12
12
2018
Statut:
ppublish
Résumé
Checkpoint inhibitors (CIs) are highly effective but can induce severe immune-related adverse events (irAEs), which cannot be predicted. We investigated whether human leukocyte antigen (HLA) genes predispose to developing of irAEs during therapy and thus hold a predictive role. We established a prospective observational single-centre study and collected data from patients with either metastatic non-small cell lung cancer (NSCLC) or metastatic melanoma, who were treated with anti-PD-1 (programmed cell death receptor 1), anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) or both CIs combined. Data include irAEs and ranges from 15th July 2016 until 10th May 2018. In addition, we performed HLA typing via next generation sequencing. We enrolled 102 patients (median [range] age, 68 [62-74] years) with metastatic cancer in our study who received CI therapy. Of these patients, 59 (58%) developed one or more irAEs, among which pruritus (n = 32 (54%)) and rash (n = 24 (41%)) had the highest rates. We did not find evidence for a single HLA gene being associated with all irAEs (all P > .05). When assessing each irAE individually, we found a significant association between HLA-DRB1*11:01 and pruritus (OR = 4.53, X The presence of two HLA alleles that are known to predispose to autoimmune diseases were associated with the development of pruritus or colitis during therapy, suggesting a genetic aetiology of irAEs. Larger genome-wide association studies should be performed to confirm our findings.
Sections du résumé
BACKGROUND
Checkpoint inhibitors (CIs) are highly effective but can induce severe immune-related adverse events (irAEs), which cannot be predicted. We investigated whether human leukocyte antigen (HLA) genes predispose to developing of irAEs during therapy and thus hold a predictive role.
METHODS
We established a prospective observational single-centre study and collected data from patients with either metastatic non-small cell lung cancer (NSCLC) or metastatic melanoma, who were treated with anti-PD-1 (programmed cell death receptor 1), anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) or both CIs combined. Data include irAEs and ranges from 15th July 2016 until 10th May 2018. In addition, we performed HLA typing via next generation sequencing.
RESULTS
We enrolled 102 patients (median [range] age, 68 [62-74] years) with metastatic cancer in our study who received CI therapy. Of these patients, 59 (58%) developed one or more irAEs, among which pruritus (n = 32 (54%)) and rash (n = 24 (41%)) had the highest rates. We did not find evidence for a single HLA gene being associated with all irAEs (all P > .05). When assessing each irAE individually, we found a significant association between HLA-DRB1*11:01 and pruritus (OR = 4.53, X
CONCLUSIONS
The presence of two HLA alleles that are known to predispose to autoimmune diseases were associated with the development of pruritus or colitis during therapy, suggesting a genetic aetiology of irAEs. Larger genome-wide association studies should be performed to confirm our findings.
Identifiants
pubmed: 30529903
pii: S0959-8049(18)31470-9
doi: 10.1016/j.ejca.2018.11.009
pii:
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
HLA-DQ beta-Chains
0
HLA-DQB1 antigen
0
Types de publication
Clinical Trial
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8-14Informations de copyright
Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.