nad a22 4500 551468211 20181215081820.0 cr unu---uuuuu 181215e20190101xx s 000 0 eng 10.5167/uzh-159412 doi 10.1016/j.ejca.2018.11.009 doi (ZORA)oai:www.zora.uzh.ch:159412 610 ddc 30529903 pmid Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors [Elektronische Daten] [Omar Hasan Ali, Fiamma Berner, David Bomze, Mirjam Fässler, Stefan Diem, Antonio Cozzio, Markus Jörger, Martin Früh, Christoph Driessen, Tobias L Lenz, Lukas Flatz] openAccess eu-repo 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. Dermatology Clinic zora Cancer Research, Oncology zora Hasan Ali Omar joint author Berner Fiamma joint author Bomze David joint author Fässler Mirjam joint author Diem Stefan joint author Cozzio Antonio joint author Jörger Markus joint author Früh Martin joint author Driessen Christoph joint author Lenz Tobias L. joint author Flatz Lukas joint author European Journal of Cancer 107:8-14 https://www.zora.uzh.ch/id/eprint/159412/1/1-s2.0-S0959804918314709-main.pdf text/html WWW-Backlink auf das Repository 1 Journal Article PeerReviewed zora SNSF/Projectfunding/PP00P3_157448/CH zora grantAgreement ZORA 856 40 https://www.zora.uzh.ch/id/eprint/159412/1/1-s2.0-S0959804918314709-main.pdf text/html WWW-Backlink auf das Repository ZORA 700 1- Hasan Ali Omar joint author ZORA 700 1- Berner Fiamma joint author ZORA 700 1- Bomze David joint author ZORA 700 1- Fässler Mirjam joint author ZORA 700 1- Diem Stefan joint author ZORA 700 1- Cozzio Antonio joint author ZORA 700 1- Jörger Markus joint author ZORA 700 1- Früh Martin joint author ZORA 700 1- Driessen Christoph joint author ZORA 700 1- Lenz Tobias L. joint author ZORA 700 1- Flatz Lukas joint author ZORA 773 0- European Journal of Cancer 107:8-14 BK010053 XK010053 XK010000 ZORA ZORA ZORA Journal Article openAccess