Endocrine toxicities of immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target two key signalling pathways related to T cell activation and exhaustion, by binding to and inhibiting cytotoxic T lymphocyte antigen 4 (CTLA4) or PD1 and its ligand PDL1. ICIs, such as nivolumab, pembrolizumab and ipilimumab, are approved for the treatment of numerous and diverse cancer types, in various combination regimens, and are now an established cornerstone of cancer therapeutics. Toxicities induced by ICIs are autoimmune in nature and are referred to as immune-related adverse events (irAEs); these events can affect any organ system in an unpredictable fashion. Importantly, irAEs can manifest as endocrinopathies involving the thyroid (hypothyroidism or thyrotoxicosis), pituitary (hypophysitis), adrenal glands (adrenal insufficiency) and pancreas (diabetes mellitus). These events are a frequent source of acute and persistent morbidity in patients treated with ICIs and can even be fatal. Over the past few years, there has been a growing understanding of the underlying pathogenesis of irAEs that has led to the development of more effective management strategies. Herein, we review the current understanding of the pathobiology, clinical manifestations and treatment approaches to endocrine toxicities arising from ICIs.

Figure 1:

Schematic of immune checkpoint inhibitor activity; anti-CTLA-4 (left) and anti-PD-1/PD-L1 (right). T cell activation requires 1) engagement of a T cell receptor (TCR) with an antigen presented in the context of a major histocompatibility complex (MHC), and 2) a second signal consisting of engagement of CD28 with B7. CTLA-4 opposes this second signal, by binding to B7 at higher affinity than CD28, thus limiting T cell activation. Blocking CTLA-4 pharmacologically, therefore “removes the brakes” on T cell activation and allows for unopposed engagement of the second signal. PD-1, a receptor on T cells, binds PD-L1, expressed on a variety of cells including tumor cells and tumor-infiltrating macrophages, which triggers a cascade of T cell inhibitor processes known as T cell exhaustion. Blocking either side of this interaction (with PD-1 or PD-L1 targeting antibodies) prevents this engagement, precludes T cell exhaustion, and permits anti-tumor activity

Figure 2:

Incidence of endocrine adverse events varies by organ affected and by type of ICI therapy. Data presented as percent of patients treated with indicated ICI therapy that develop the indicated hormonal dysfunction. AI, adrenal insufficiency. Adapted from data reported in de Filette et al, 2019.

Figure 3:

Onset of endocrinopathy can occur at any time after ICI initiation. Median time (in weeks) to onset of AI, diabetes, thyroid dysfunction and hypophysitis, with interquartile range and range indicated by boxes and whiskers, respectively. AI, adrenal insufficiency. Adapted from data reported in Tan et al, 2019.

Figure 4:

A) Percentage of patients with ICI-associated hypophysitis with adrenal, thyroid, or gonadal axes affected. B) Percentage of patients with the indicated number of hormonal axes affected. The majority of patients have 2-3 axes affected. Adapted from data reported in Tan et al, 2019.