Omar Hasan Ali1, Fiamma Berner2, David Bomze2, Mirjam Fässler2, Stefan Diem3, Antonio Cozzio4, Markus Jörger5, Martin Früh5, Christoph Driessen5, Tobias L Lenz6, Lukas Flatz7. 1. Department of Dermatology, University Hospital of Zürich, CH-8091, Zürich, Switzerland; Institute of Immunobiology, Kantonsspital St.Gallen, CH-9007, St. Gallen, Switzerland. 2. Institute of Immunobiology, Kantonsspital St.Gallen, CH-9007, St. Gallen, Switzerland. 3. Department of Oncology and Hematology, Kantonsspital St. Gallen, CH-9007, St. Gallen, Switzerland; Department of Oncology and Hematology, Hospital of Grabs, CH-9472, Grabs, Switzerland. 4. Department of Dermatology, Kantonsspital St. Gallen, CH-9007, St. Gallen, Switzerland. 5. Department of Oncology and Hematology, Kantonsspital St. Gallen, CH-9007, St. Gallen, Switzerland. 6. Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, D-24306, Plön, Germany. 7. Department of Dermatology, University Hospital of Zürich, CH-8091, Zürich, Switzerland; Institute of Immunobiology, Kantonsspital St.Gallen, CH-9007, St. Gallen, Switzerland; Department of Oncology and Hematology, Kantonsspital St. Gallen, CH-9007, St. Gallen, Switzerland; Department of Dermatology, Kantonsspital St. Gallen, CH-9007, St. Gallen, Switzerland. Electronic address: lukas.flatz@kssg.ch.
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.
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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