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

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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-C889-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-C88A-1
Genre: Journal Article

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1-s2.0-S0959804918314709-main.pdf (Publisher version), 516KB
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 Creators:
Hasan Ali, Omar, Author
Berner, Fiamma, Author
Bomze, David, Author
Fässler, Mirjam, Author
Diem, Stefan, Author
Cozzio, Antonio, Author
Jörger, Markus, Author
Früh, Martin, Author
Driessen, Christoph, Author
Lenz, Tobias L.1, Author              
Flatz, Lukas, Author
Affiliations:
1Emmy Noether Research Group Evolutionary Immunogenomics, Department Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_2068286              

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Free keywords: Cancer immunotherapy, Immune-related adverse events, Human leukocyte antigen, Therapeutic marker, Non–small cell lung cancer, Melanoma
 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.

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Language(s): eng - English
 Dates: 2018-08-222018-11-012018-12-072019
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.ejca.2018.11.009
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Title: European Journal of Cancer
Source Genre: Journal
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Publ. Info: Oxford, UK : Pergamon
Pages: - Volume / Issue: 107 Sequence Number: - Start / End Page: 8 - 14 Identifier: ISSN: 0959-8049
CoNE: https://pure.mpg.de/cone/journals/resource/111022849554052