Thyroid Immune Related Adverse Events Following Immune Checkpoint Inhibitor Treatment

Abstract

The efficacy of immune checkpoint inhibitor (ICI) treatment rivals traditional anti-tumor therapies and in most cases results in significantly less drug related toxicity. However, ICI-use can result in a myriad of immune and inflammatory side effects termed immune related adverse events (irAEs). Thyroid irAEs are the most common endocrine toxicity related to ICI-treatment. In affected patients, permanent thyroid dysfunction can result, necessitating lifelong thyroid hormone replacement and long-term clinical follow-up is required. Prior to this candidature, clinical descriptions of thyroid irAEs were predominately based on small, heterogeneous patient cohorts and little was known about the underlying pathogenesis responsible for their development. This thesis produced a detailed phenotypic report of 1246 patients with melanoma undergoing ICI-treatment. We clearly showed that prevalence of thyroid irAEs was substantially higher than previously reported, and that most patients developed subclinical disease only. We demonstrated that overt thyrotoxicosis had distinct clinical features from other thyroid irAE presentations and was uniquely associated with improvements in survival. We prospectively measured anti-thyroid antibody levels and showed they were highly specific for identifying patients likely to experience a thyroid irAE. Our antibody work was complemented by preclinical studies including development of an animal model to test for autoantibodies against novel thyroid antigens, a genetic study to test for an association with FLT3 gene polymorphism and immunophenotyping peripheral blood to identify key immune cell populations involved in the pathogenesis of thyroid irAEs. In totality, the work in this thesis significantly advances understanding of thyroid irAEs and the mechanisms underpinning their development.