The side effects of immune checkpoint inhibitor therapy on the endocrine system

Abstract

Immune checkpoint inhibitors (ICIs) are a relatively newer class of drugs approved for the treatment of malignancies such as melanoma, renal, bladder and lung cancer. Immune-related adverse events (IrAEs) involving the endocrine system are a common side effect of these drugs. The spectrum of endocrine adverse events varies by the drug class. Cytotoxic T-lymphocyte-associated antigen-4 inhibitors commonly cause hypophysitis/hypopituitarism, whereas the incidence of thyroid disease is higher with programmed cell death (PD)-1/ ligand (PD-L) protein 1 inhibitors. The focus of this review is to describe the individual endocrinopathies with their possible mechanisms, signs and symptoms, clinical assessment and disease management. Multiple mechanisms of IrAEs have been described in literature including type II/IV hypersensitivity reactions and development of autoantibodies. Patients with pre-existing autoimmune endocrine diseases can have disease exacerbation following ICI therapy rather than de novo IrAEs. Most of the endocrinopathies are relatively mild, and timely hormone replacement therapy allows continuation of ICIs. However, involvement of the pituitary-adrenal axis could be life-threatening if not recognized. Corticosteroids are helpful when the pituitary-adrenal axis is involved. In cases of severe endocrine toxicity (grade 3/4), ICIs should be temporarily discontinued and can be restarted after adequate hormonal therapy. Endocrinologists and general internists need to be vigilant and maintain a high degree of awareness for these adverse events.

Keywords: Adrenal insufficiency; autoimmune diabetes; autoimmune endocrinopathy; corticosteroids; hormone replacement; hypophysitis; hypothyroidism; immune checkpoint inhibitors.

Fig. 1

CTLA-4 inhibitors mechanism of action. (A) Inactivated T cell: Binding of B7 with CTLA-4 instead of CD28 keeps T cell inactivated by blocking co-stimulation. (B) Activated T cell: CTLA-4 inhibitors like ipilimumab bind with CTLA-4 on T cells thereby releasing B7 to bind with CD28 for co-stimulating and activating T cells. TCR, T cell receptor; MHC, major histocompatibility complex; APC, antigen presenting cell; CTLA-4, cytotoxic T-lymphocyte–associated antigen-4. Source: Refs ,.

Fig. 2

PD-1/PDL-1 inhibitors mechanism of action. (A) Inactivated T cell: Binding of PD-1 on T-cell with PD-L1 on tumour cell keeps T cell inactivated. (B) Activated T cell: Anti PD-1 or PD-L1 antibodies prevent binding of PD-1 with PD-L1 to keep T cell activated. PD-1, programmed cell death protein-1; PD-L1, PD ligand-1. Source: Refs ,.