- •Specific human leucocyte antigen types were correlated with pituitary immune-related adverse events (irAEs).
- •This was seen especially in patients with secondary adrenal insufficiency.
- •This information may enable effective prediction of irAEs.
- •These data could enable safer treatment with immune checkpoint inhibitors.
- •This study provides clues regarding the aetiology of these adverse events.
Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious ‘pituitary irAE.’ However, its precise mechanism remains unclear, and no definitive predictive markers have been reported.
Patients and methods
We enrolled and studied 11 patients with advanced cancer (aged 39–70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls.
Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non–small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013).
HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.
Abbreviations:CTLA4 (cytotoxic T-lymphocyte–associated antigen-4), HLA (human leucocyte antigen), ICPis (immune checkpoint inhibitors), IL (interleukin), irAE (immune-related adverse event), MRI (magnetic resonance imaging), PD-1 (programmed cell death-1), PD-L1 (programmed death-ligand-1), Th (helper T), T1DM (type 1 diabetes mellitus)
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Published online: March 28, 2020
Accepted: February 28, 2020
Received in revised form: February 24, 2020
Received: July 3, 2019
© 2020 Elsevier Ltd. All rights reserved.
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- Consideration regarding immune checkpoint inhibitor–induced secondary adrenal insufficiency in patients lacking human leucocyte antigen-DR15European Journal of CancerVol. 143
- PreviewWe read the article entitled ‘Human leucocyte antigen DR15, a possible predictive marker for immune checkpoint inhibitor-induced secondary adrenal insufficiency’ by Seiichi Yano et al.  with great interest. The authors reported significantly higher prevalence of human leucocyte antigen (HLA)-DR15, B52, and Cw12 in 11 patients with immune checkpoint inhibitor (ICPi)–induced secondary adrenal insufficiency as compared with Japanese healthy controls. Furthermore, they presented the possibility of HLA-DR15 as a predictive marker of a pituitary immune-related adverse event (irAE).