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Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors

Omar Hasan Ali, Fiamma Berner, David Bomze, Mirjam Fässler, Stefan Diem, Antonio Cozzio, Markus Joerger, Martin Früh, Christoph Driessen, Tobias L Lenz & Lukas Flatz

abstract

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 = 9.45, P < .01) as well as a nominally significant additive association between HLA-DQB1*03:01 and colitis (OR = 3.94, X = 5.67, P = .017).

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.
   
citation Hasan Ali O, Berner F, Bomze D, Fässler M, Diem S, Cozzio A, Joerger M, Früh M, Driessen C, Lenz T L, Flatz L. Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors. Eur J Cancer 2018; 107:8-14.
   
type journal paper/review (English)
date of publishing 07-12-2018
journal title Eur J Cancer (107)
ISSN electronic 1879-0852
pages 8-14
PubMed 30529903
DOI 10.1016/j.ejca.2018.11.009