Characterisation and Prediction of Checkpoint Inhibitor Associated Autoimmune Diabetes Mellitus

Abstract

With the expanding use of immune checkpoint inhibitors in cancer therapy, there is growing interest in characterising and predicting the severe immune related adverse events that can arise as a complication of this therapy. Checkpoint inhibitor associated autoimmune diabetes mellitus (CIADM) is one such immune related adverse event and has been reported in case series to date as a novel form of fulminant type 1 diabetes. This thesis aims to characterise the clinical and immune phenotype of CIADM to improve identification and management of CIADM and investigate potential avenues for prevention of CIADM.

In a multicentre case series (Chapter 2) the clinical phenotype of patients with CIADM is detailed, along with the key hallmarks of absolute insulin deficiency, rapid pancreatic volume loss, exocrine insufficiency and variable degree of type 1 diabetes autoantibody positivity. A systematic review (Chapter 3) was subsequently conducted which demonstrated what features were most prominent in CIADM to allow for formation of clinical diagnostic criteria. Finally in Chapter 6, clinical guidance is provided based on multidisciplinary consensus to improve the identification and care of patients treated with immune checkpoint inhibitors who develop hyperglycaemia on treatment.

Using longitudinal blood, serum samples and radiological data in a case-control study, potential biomarkers for CIADM are identified in Chapter 4. Immune cell subsets, pancreatic volume, and Type 1 diabetes autoantibodies at baseline were found to be predictive of CIADM with a ROC curve AUC of 0.96. Whilst data on CIADM in humans has largely been limited to systemic markers, using a mouse model of CIADM, the islet immune infiltrate and endocrine cells are further profiled in Chapter 5 and potential key local immune cell types in CIADM are identified. Together, these studies provide a foundation for future work in prediction and prevention of CIADM.