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

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 nonesmall cell lung cancer (NSCLC) or metastatic melanoma, who were treated with antiePD-1 (programmed cell death receptor 1), anti-CTLA4 (cytotoxic T-lymphocyteeassociated 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 [62e74] 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 Z 32 (54%)) and rash (n Z 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 Z 4.53, X 2 1,95 Z 9.45, P < .01) as well as a nominally

Tumor mutational burden quantification from targeted gene panels: major advancements and challenges

“…The Friends and QuIP initiatives for TMB harmonization recommended to include as much relevant genetic and molecular information as possible in these panels, to avoid the need to re-biopsy the patient for further information. In line with this recommendation, we propose to also include in gene panels for TMB quantification other potential immunotherapy biomarkers but also negative predictors of immunotherapy response [69,70] and variants predisposing to adverse reaction to immunotherapy [71,72]. These and other recommendations which emerge from the studies reviewed here, including the one from the TMB Harmonization Working Group, are summed up in Additional file 6: Table S6.…”

Clinical Features of Liver Injury Induced by Immune Checkpoint Inhibitors in Japanese Patients

“…A previous report evaluating the relationship between irAEs and HLA types showed that pruritus and colitis were associated with HLA-DRB1 * 11 : 01 and HLA-DQB1 * 03 : 01, respectively [40]. However, the association between hepatic irAEs and HLA types has not been demonstrated yet.…”

Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes

“…They are significantly associated with a large number of autoimmune diseases and may also be associated with irAEs. There is evidence that specific individual HLA types were enriched in colitis , pruritis , rheumatoid arthritis and hypophysitis . In conventional T1DM, the highest risk derives from the heterozygous combination of DR3‐DQ2 and DR4‐DQ8 with increased risk still conferred by each of these alleles on their own .…”