Pancreatic volume and immune biomarkers predict checkpoint inhibitor-associated autoimmune diabetes in humans

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Abstract

BACKGROUND. Checkpoint inhibitor-associated autoimmune diabetes (CIADM) is a rare but life-altering complication of immune checkpoint inhibitor (ICI) therapy. Biomarkers that predict type 1 diabetes (T1D) are unreliable for CIADM. AIM. To identify biomarkers for prediction of CIADM. METHODS. From our prospective biobank, 14 CIADM patients who had metastatic melanoma treated with anti-PD-1 ± anti-CTLA4 were identified. Controls were selected from the same biobank, matched 2:1. Pre-treatment, on-ICI and post-CIADM serum and peripheral blood mononuclear cells (PBMCs) were analysed. Serum was analysed for T1D autoantibodies, C-peptide, glucose and cytokines. PBMCs were profiled using flow cytometry. Pancreatic volume was measured using CT volumetry. RESUTLS. Before treatment, CIADM patients had smaller pancreatic volume (27% reduction, p=0.044) and higher anti-GAD antibody titres (median 2.9 versus 0, p=0.01). They had significantly higher baseline proportions of Th17 helper cells (p=0.03), higher CD4+ central memory cells (p=0.04) and lower naïve CD4+ cells (p=0.01). With ICI treatment, greater declines in pancreatic volume were seen in CIADM patients (p<0.0001). Activated CD4+ subsets increased significantly in CIADM and controls with immune-related adverse effects (IRAE) but not controls without IRAE. Using only pre-treatment results, pancreatic volume, anti-GAD antibody titre and baseline immune flow profile were highly predictive of CIADM development, with an area under the curve (AUC) of >0.96. CONCLUSIONS. People who develop CIADM are immunologically predisposed and have antecedent pancreatic and immunological changes that accurately predict disease with excellent sensitivity. These biomarkers could be used to guide ICI use, particularly when planning treatment for low-risk tumours. FUNDING. JEG is supported by NHMRC Investigator grant 2033228. AMM by NHMRC Investigator grant 2009476 and GVL by NHMRC Investigator grant 2007839.

Authors

Linda Wu, John M. Wentworth, Christopher Liddle, Nicole Fewings, Matteo Carlino, David A. Brown, Roderick Clifton-Bligh, Georgina V. Long, Richard A. Scolyer, Nicholas Norris, Sarah C. Sasson, Venessa H.M. Tsang, Alexander M. Menzies, Jenny E. Gunton