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

Hasan Ali, Omar et al.

European journal of cancer. Volume 107 (2019); pp 8-14 -- Elsevier

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  • Title:
    Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors
  • Author: Hasan Ali, Omar;
    Berner, Fiamma;
    Bomze, David;
    Fässler, Mirjam;
    Diem, Stefan;
    Cozzio, Antonio;
    Jörger, Markus;
    Früh, Martin;
    Driessen, Christoph;
    Lenz, Tobias L.;
    Flatz, Lukas
  • Found In: European journal of cancer. Volume 107 (2019); pp 8-14
  • Journal Title: European journal of cancer
  • Subjects: Cancer--Périodiques; Neoplasms--Periodicals; Cancer--Periodicals; Cancer; Periodicals; Tumors; Cancer immunotherapy--Immune-related adverse events--Human leukocyte antigen--Therapeutic marker--Non–small cell lung cancer--Melanoma; Electronic journals; Dewey: 616.994
  • Rights: legaldeposit
  • Publication Details: Elsevier
  • Abstract: 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.


    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 2 1, 95 = 9.45, P  < .01) as well as a nominally significant additive association between HLA-DQB1*03:01 and colitis (OR = 3.94, X 2 1, 95 = 5.67, P  = .017).


    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.


    Carriers of HLA-DRB1*11:01 likely develop pruritus during immunotherapy.

    Carriers of HLA-DQB1*03:01 are predisposed to develop colitis during immunotherapy.

    There is a trend between HLA-DRB1*01:01 and skin rash during immunotherapy.

    This is the first study showing a link between HLA and immune-related adverse events.

  • Identifier: System Number: LDEAvdc_100076935285.0x000001; Journal ISSN: 0959-8049; 10.1016/j.ejca.2018.11.009
  • Publication Date: 2019
  • Physical Description: Electronic
  • Shelfmark(s): ELD Digital store

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