Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors

Abstract

BackgroundPituitary dysfunction is a life-threatening immune-related adverse event (irAE) induced by immune checkpoint inhibitors (ICIs). To date, it is not possible to identify patients who may develop pituitary irAEs prior to ICI treatment. The aim of this study was to characterize the predisposition for ICI-induced pituitary irAEs by analyzing anti-pituitary antibodies (APAs) and human leukocyte antigens (HLAs).MethodsIn this case–control study, APAs and HLA alleles were analyzed in 62 patients (17 who developed ICI-induced isolated adrenocorticotropic hormone deficiency (ICI-IAD), 5 who developed ICI-induced hypophysitis (ICI-H) and 40 who did not develop pituitary irAEs) treated with ICIs between November 2, 2015, and March 31, 2020, at Nagoya University Hospital. The main outcome measures in this study were the association between the development of pituitary irAEs with APAs at baseline and after treatment and HLA alleles.ResultsEleven of 17 (64.7%) patients who developed ICI-IAD had APAs at baseline, whereas APAs were positive only in 1 of 40 (2.5%) control patients. Although APAs were negative at baseline in all patients who developed ICI-H, they had become positive before the onset of ICI-H in 3 of 4 patients several weeks after ipilimumab administration. At the onset of ICI-IAD and ICI-H, APAs were positive in 15 of 17 (88.2%) and 4 of 5 (80%) patients, respectively. The prevalence of HLA-Cw12, HLA-DR15, HLA-DQ7, and HLA-DPw9 was significantly higher in patients with ICI-IAD, whereas that of HLA-Cw12 and HLA-DR15 was significantly higher in patients with ICI-H than in controls.ConclusionsThis study showed distinct and overlapped patterns of APAs and HLA alleles between ICI-IAD and ICI-H. Our findings also showed that positive APAs at baseline and after treatment, together with susceptible HLA alleles, could become predictive biomarkers for ICI-IAD and ICI-H, respectively.Trial registration numberUMIN000019024.

Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline

“…Pituitary antibodies assayed by indirect immunofluorescence on human pituitary sections were found in 15 out of 17 (88.2%) and in 4 out of 5 (80%) patients treated with anti-PD1 or anti-CTLA-4, respectively (37). The pituitary autoantigen(s) has not been identified.…”

Human Leukocyte Antigens and Biomarkers in Type 1 Diabetes Mellitus Induced by Immune-Checkpoint Inhibitors

“…The allele and haplotype frequencies were compared to those of non-IR with ICI therapy (referred to as ICI-controls) [ 7 ], and those of healthy Japanese controls [ 16 , 17 ]. In a confirmatory set, HLA-DPB1 was genotyped using a Luminex system with WAKFlow HLA typing kits (Wakunaga Pharmaceutical, Hiroshima, Japan), as described previously [ 18 ].…”

Association between germ-line HLA and immune-related adverse events

“…In recent years, multiple studies have already unraveled the positive association between irAEs and HLA class I as well as HLA class II alleles, including HLA-DRB1*11:01 and pruritus, HLA-B27 and autoimmune encephalitis, HLA-DR15, HLA-Cw12 and adrenal insufficiency, HLA-Cw12, HLA-DR15, HLA-DQ7, and HLA-DPw9 with hypophysitis, HLA-DR4-DR53 and HLA-DR15 with thyroiditis, and HLA-B*35 and DRB1*11 with pneumonitis ( 18 – 21 , 23 , 32 ). The HLA- autoimmune disease association may vary according to different races/ethnicities.…”