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

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

doi:10.1016/j.ejca.2018.11.009

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Journal Article

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

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Lenz, Tobias L.
Emmy Noether Research Group Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

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Citation

Hasan Ali, O., Berner, F., Bomze, D., Fässler, M., Diem, S., Cozzio, A., et al. (2019). Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors. European Journal of Cancer, 107, 8-14. doi:10.1016/j.ejca.2018.11.009.

Cite as: https://hdl.handle.net/21.11116/0000-0002-C889-2

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, X21,95 = 9.45, P < .01) as well as a nominally significant additive association between HLA-DQB1*03:01 and colitis (OR = 3.94, X21,95 = 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.