Immune Checkpoint Inhibitors: Review and Management of Endocrine Adverse Events

Abstract

: In recent years, immune checkpoint inhibitors have emerged as effective therapies for advanced neoplasias. As new checkpoint target blockers become available and additional tumor locations tested, their use is expected to increase within a short time. Immune-related adverse events (irAEs) affecting the endocrine system are among the most frequent and complex toxicities. Some may be life-threatening if not recognized; hence, appropriate guidance for oncologists is needed. Despite their high incidence, endocrine irAEs have not been fully described for all immunotherapy agents available. This article is a narrative review of endocrinopathies associated with cytotoxic T lymphocyte-associated antigen-4, blockade of programmed death receptor 1 and its ligand inhibitors, and their combination. Thyroid dysfunction is the most frequent irAE reported, and hypophysitis is characteristic of ipilimumab. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for clinical management are suggested. Heterogeneous terminology and lack of appropriate resolution criteria in clinical trials make adequate evaluation of endocrine AEs difficult. It is necessary to standardize definitions to contrast incidences and characterize toxicity patterns. To provide optimal care, a multidisciplinary team that includes endocrinology specialists is recommended.

Implications for practice: Immune checkpoint inhibitors are already part of oncologists' therapeutic arsenal as effective therapies for otherwise untreatable neoplasias, such as metastatic melanoma or lung cancer. Their use is expected to increase exponentially in the near future as additional agents become available and their approval is extended to different tumor types. Adverse events affecting the endocrine system are among the most frequent and complex toxicities oncologists may face, and some may be life-threatening if not recognized. This study reviews endocrinopathies associated to immune checkpoint inhibitors available to date. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for management are proposed.

Keywords: Autoimmune hypophysitis; Cytotoxic T-lymphocyte antigen 4; Monoclonal antibodies; Programmed cell death 1 receptor; Thyroiditis.

Figure 1.

Timing pattern of endocrine adverse events.

Figure 2.

Melanocyte differentiation pathway dependent on MSHα and ACTH. MSHα and ACTH can both bind to MC2R. MC2R is coupled to G-protein α-s, which stimulates adenylate cyclase type I, increasing production of cAMP, hence activating PKA. PKA phosphorylates CREB1, which in turn activates the expression of MITF. MITF regulates transcription of genes coding mitochondrial ribosomal proteins through interactions with TYRP1 and MLANA. Abbreviations: ACTH, adrenocorticotropic hormone; AMP, adenosine monophosphate; CREB1, cAMP response element-binding protein 1; MC2R, melanocortin 2 receptor; MITF, microphthalmia-associated transcription factor; MLANA, melan-A; MSHα, melanocyte-stimulating hormone α; PKA, cAMP-dependent protein kinase; TYRP1, tyrosinase-related protein 1.

Figure 3.

Brain magnetic resonance image of a patient with CTLA4 mAb-induced hypophysitis. Sagital T1-weighted postcontrast image showing an enlarged and intensely enhancing pituitary gland as well as thickening of the stalk affecting the optic quiasm.

Figure 4.

Suggested management of serious endocrine adverse events. Abbreviations: ACTH, adrenocorticotropic hormone; aGADAb, anti-glutamic acid decarboxilase antibodies; aIA2Ab, anti-tyrosine phosphatase IA2 antibodies; DKA, diabetic ketoacidosis; FSH, follicle-stimulating hormone; IGF-1, insulin-like growth factor-1; LH, luteinizing hormone; MRI, magnetic resonance imaging; SS, saline solution 0.9%; T₄, thyroxine; TSH, thyroid-stimulating hormone.

Figure 5.

Suggested management of thyroid dysfunction. Abbreviations: CHF, congestive heart failure; T₄, thyroxine; TPOAb, anti-peroxidase antibodies; TSH, thyroid-stimulating hormone; TSIAb, anti-TSH receptor antibodies.