Endocrine complications of immunotherapies: a review

Abstract

Use of immune checkpoint inhibitors in cancer treatment has increased vastly over the past decade, as both single and combination agent therapies. While having a positive impact on survival rates, adverse effects have been noted, with endocrine effects in around 10% of patients. Thyroid disease and hypophysitis are the most commonly encountered, with diabetes mellitus and primary adrenal insufficiency also reported, as well as more rare endocrinopathies. Patient and clinician education to raise awareness of these effects, as well as regular monitoring to enable early recognition, diagnosis and prompt treatment of the immune side effects, are key. In this review, we discuss the aetiology, presentation and management of the endocrine complications of immunotherapies that are relevant to the general physician, as well as highlighting important areas where further research is still needed.

Keywords: cancer; endocrine; hypophysitis; immunotherapy; thyroid.

Fig 1.

Simplified illustration of the mechanism of checkpoint inhibitor modulation of the immune response to cancer cells. a) Normal physiological state. In the unaltered physiological state, detection of cancer cell antigens, either via antigen-presenting cells or cancer cells themselves, causes T-cell activation. Pictured are two physiological mechanisms that reduce exaggerated immune response, but also immunosurveillance and therefore elimination of cancer cells. (1) CTLA-4 outcompetes CD-28 to bind to CD-80. Instead of further activation by CD-28, CTLA-4 sends inhibitory signals to deactivate T-cells. (2) Binding of PD-L-1 on the cancer cell or antigen-presenting cell to PD-1 on a T-cell activates inhibitory signals to immune response and encourages apoptosis of immune cells. b) State with checkpoint inhibitor therapy. Checkpoint inhibitor therapy acts on both mechanisms via three targets. (1) Anti-CTLA-4 mAb binds to CTLA-4, resulting in subsequent promotion of T-cell activation and survival by the CD-28 pathway. (2) Anti-PD-1 mAb binds to PD-1 on T-cells, preventing a negative feedback pathway. (3) Anti-PD-L-1 mAb binds to PD-L-1 on cancer cells, preventing the same negative feedback. CTLA-4 = cytotoxic T-lymphocyte antigen 4; mAb = monoclonal antibody; PD-1 = protein death 1; PD-L-1 = protein death ligand 1.

Fig 2.

Management of thyroid dysfunction secondary to checkpoint inhibitors: a clinical guide. Information as per Society for Endocrinology guidelines and UK Oncology Nursing Society.^, Ab = antibody; T4 = thyroxine; TFT = thyroid function test; TSH = thyroid-stimulating hormone; TSHR = thyroid-stimulating hormone receptor.

Fig 3.

Management of hypophysitis secondary to checkpoint inhibitors: a clinical guide. Information as per Society for Endocrinology guidelines and UK Oncology Nursing Society. Ab = antibody; ACTH = adrenocorticotrophic hormone; AI = adrenal insufficiency; BP = blood pressure; FSH = follicular stimulating hormone; GH = growth hormone; HCT = haematocrit; IGF-1 = insulin-like growth factor 1; IM = intramuscular; IV = intravenous; LH = luteinising hormone; PSA = prostate specific antigen; T4 = thyroxine; T3 = triiodothyronine; TFT = thyroid function test; TSH = thyroid-stimulating hormone; TSHR = thyroid-stimulating hormone receptor.