Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints

Abstract

Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with cancer. The US Food and Drug Administration has approved several immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi therapy. Hypophysitis, thyroid dysfunction, insulin-deficient diabetes mellitus, and primary adrenal insufficiency have been reported as irAEs due to ICPi therapy. Hypophysitis is particularly associated with anti-CTLA-4 therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1 therapy. Diabetes mellitus and primary adrenal insufficiency are rare endocrine toxicities associated with ICPi therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1 therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central adrenal insufficiency and primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with tumor response to ICPi therapy.

Figure 1.

Model of intrinsic and extrinsic actions of CTLA-4. CTLA-4 inhibits T-cell activity by a number of intrinsic and extrinsic mechanisms. CTLA-4 expressed on conventional T-cells interacts with its ligands CD80 and CD86 to initiate inhibitory signaling, enhance adhesion, and compete with CD28 to block interaction between CD28 and CD80/CD86. CTLA-4 can deplete its ligands (CD80 and CD86) by removing them from APCs through trans-endocytosis. CTLA-4 can also act as a ligand to activate CD80 and CD86 on APCs to induce IDO, stimulate the production of regulatory cytokines such as TGF-β, and trigger APC or T-cell inhibition. CTLA-4 on Tregs enhances the inhibitory action of Tregs on conventional T-cells. MHC, major histocompatibility complex. [© 2019 Illustration Presentation ENDOCRINE SOCIETY].

Figure 2.

Mechanisms of PD-1 action on T-cells. Engagement of PD-1 with its ligand PD-L1 induces an intracellular inhibitory pathway to inhibit costimulatory CD28-activated PI3K pathways. As a result, gluconeogenesis and glucose uptake decrease, leading to T-cell exhaustion. Bcl-xL, B-cell lymphoma-extra large; PD-L1, programmed death-ligand 1. [© 2019 Illustration Presentation ENDOCRINE SOCIETY].

Figure 3.

Approximate map locations of CTLA-4 SNPs frequently associated with autoimmune endocrinopathies. SNPs present in both coding and noncoding regions. Most SNPs occur in nontranslated regions. The CTLA-4 gene has four exons, represented by the boxes. Blue boxes represent translated regions. [© 2019 Illustration Presentation ENDOCRINE SOCIETY].

Figure 4.

Incidence of thyroid dysfunction and hypophysitis induced by different ICPi regimens. The highest incidence of thyroid dysfunction is associated with combination therapy with anti-CTLA-4 and anti-PD-1 therapy. In monotherapy groups, the incidence of hypothyroidism and hyperthyroidism is higher with anti-PD-1 monotherapy than with anti-CTLA-4 or anti-PD-L1 monotherapy. On the other hand, the incidence of hypophysitis is higher with anti-CTLA-4 monotherapy than with anti-PD-1 or anti-PD-L1 monotherapy. With data from Barroso-Sousa R, Barry WT, Garrido-Castro AC, et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol. 2018;4(2):173–182. [© 2019 Illustration Presentation ENDOCRINE SOCIETY].

Figure 5.

ICPi-related hypophysitis. Brain MRI showing development and resolution of ICPi-related hypophysitis in a 54-year-old woman with metastatic lung adenocarcinoma treated with nivolumab and a history of primary hypothyroidism on thyroid hormone replacement with levothyroxine. (a) Brain MRI, obtained 4 mo prior to nivolumab initiation, showed a normal-appearing pituitary gland (white arrow). Two wk after her third dose of nivolumab (3 mo after nivolumab initiation), she presented to oncology clinic with a 1-wk history of headache, nausea, anorexia, fatigue, generalized weakness, and lightheadedness. She was admitted to the hospital for further evaluation and management. Laboratory testing demonstrated new onset of hyponatremia (sodium 118 mmol/L; reference range, 135 to 145 mmol/L), low 0800 h cortisol (0.8 μg/dL; reference range, 6 to 24 μg/dL), low ACTH (<5.0 pg/mL; reference range, 10 to 60 pg/mL), low TSH (0.21 mIU/L; reference range, 0.50 to 5.00 mIU/L), and low-normal free T4 (1.0 ng/dL; reference range, 0.9 to 1.7 ng/dL) while on her baseline dose of levothyroxine. These laboratory findings were most consistent with central adrenal insufficiency and new onset of central hypothyroidism. Cosyntropin stimulation test demonstrated a suboptimal rise in cortisol from 0.8 to 10.3 μg/dL 60 min after administration of IV cosyntropin 250 μg, confirming adrenal insufficiency. (b) Brain MRI postgadolinium contrast, obtained the d after she presented to clinic, showed a bulky, diffusely enlarged, hyperenhancing pituitary gland (white arrow) with stalk thickening, consistent with nivolumab-induced hypophysitis. She was started on replacement dose hydrocortisone (30 mg total daily in divided doses), and her levothyroxine dose was increased, with normalization of her sodium within 24 h of her first dose of hydrocortisone. Interestingly, she developed DI on the fourth d of her hospitalization, with a 24-h urine output of 7.3 L, serum sodium of 148 mmol/L, urine osmolality of 123 mOsm/kg water (reference range, 390 to 1093 mOsm/kg water). She was started on desmopressin (DDAVP) with symptomatic control of her DI and normalization of her sodium. (c) Brain MRI, obtained 2 mo after her initial presentation with hypophysitis, showed resolution of pituitary enlargement (white arrow). She had partial resolution of her DI and was able to stop DDAVP 6 mo after it was diagnosed. Two y after her hypophysitis, her central adrenal insufficiency and hypothyroidism persist. [© 2019 Illustration Presentation ENDOCRINE SOCIETY].

Figure 6.

ICPi-related adrenalitis. A 59-year-old man with stage IIIB/IV malignant melanoma was started on ipilimumab therapy. (A) Coronal view and (C) axial view. Baseline abdominal CT 1 mo prior to ipilimumab initiation showed normal-appearing bilateral adrenal glands (red ovals). Six d after his first ipilimumab dose, he developed a pruritic maculopapular rash attributed to ipilimumab. He was treated with topical triamcinolone and a 3-d course of methylprednisolone PO. Three wk after his second dose of ipilimumab, he presented to the emergency department with epigastric pain radiating to the back, nausea, and vomiting. (B) Coronal view and (D) axial view. Abdominal CT scan showed bilateral enlarged adrenal glands (red ovals) with preserved contours, consistent with adrenalitis; no other radiographic abnormalities were seen. ACTH and cortisol drawn at 0900 h were 38 pg/mL (reference range, 7.2 to 68 pg/mL) and 20.8 μg/dL (reference range, 6.0 to 18.4 μg/dL), respectively, and sodium and potassium levels were unremarkable. He was treated with prednisone 60 mg PO daily for concern for ICPi-related abdominal pain and was tapered over the course of several wk to 20 mg PO daily. Four wk after his presentation with abdominal pain, cosyntropin stimulation test for aldosterone showed no rise in aldosterone (<4.0 ng/dL at baseline; <4.0 ng/dL 60 min after cosyntropin 250 μg IV administration), concerning for PAI. He was started on fludrocortisone 100 μg PO daily. He also subsequently developed ipilimumab-related hypophysitis complicated by central hypothyroidism requiring levothyroxine supplementation; pituitary MRI confirmed new pituitary enlargement. Abdominal MRI 2 mo after his presentation of abdominal pain showed resolution of bilateral adrenal enlargement, with normal-appearing bilateral adrenal glands. He remains on replacement corticosteroid doses 3 mo after his presentation of abdominal pain. [© 2019 Illustration Presentation ENDOCRINE SOCIETY].