Toripalimab-associated diabetes mellitus: a case report from the community of Southern China

in Endocrinology, Diabetes & Metabolism Case Reports
Authors:
Wenxin Zhang Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China

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Wenqiong Xu Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China

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Correspondence should be addressed to W Xu; Email: ndyfy00295@ncu.edu.cn
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Summary

Immune checkpoint inhibitors (ICPis) are novel immunotherapy drugs for a variety of cancers. Toripalimab is one of the ICPis that selectively blocks programmed death 1 (PD-1) and has been used for the treatment of malignant cancers in the hospitals of China. But with the widespread use of ICPis, some of the adverse reactions have gradually appeared. One of the most serious side effects is diabetes mellitus which is a relatively rare immune-related adverse event (irAEs) with life-threatening complications. We report a case of diabetes after the administration of toripalimab for the treatment of melanoma in southern China. To our knowledge, this is a rare case of diabetes occurring during toripalimab therapy, there is only one similar case reported in China so far. As China has a high morbidity of malignant cancer, a significant number of patients could be affected by the adverse reactions of using ICPis. Therefore, when ICPis are administrated, it is very important for clinicians to pay attention to one of the serious side effects – diabetes mellitus. Insulin therapy is often necessary after the diagnosis of ICPis-related diabetes, which has been proved as an effective method to prevent diabetic ketoacidosis (DKA) and other life-threatening complications in these patients.

Learning points

  • Toripalimab can cause the diabetes mellitus.

  • ICPis-related diabetes is treated primarily with insulin.

  • Immune checkpoint inhibitors cause diabetes by primarily destroying islet β cells.

  • There is not enough evidence to demonstrate that diabetic autoantibodies are related to diabetes caused by ICPis.

  • In addition to focusing on the efficacy of PD-1 inhibitor therapy, it is also necessary to pay attention to its adverse reactions, such as ICPis-related diabetes mellitus.

Abstract

Summary

Immune checkpoint inhibitors (ICPis) are novel immunotherapy drugs for a variety of cancers. Toripalimab is one of the ICPis that selectively blocks programmed death 1 (PD-1) and has been used for the treatment of malignant cancers in the hospitals of China. But with the widespread use of ICPis, some of the adverse reactions have gradually appeared. One of the most serious side effects is diabetes mellitus which is a relatively rare immune-related adverse event (irAEs) with life-threatening complications. We report a case of diabetes after the administration of toripalimab for the treatment of melanoma in southern China. To our knowledge, this is a rare case of diabetes occurring during toripalimab therapy, there is only one similar case reported in China so far. As China has a high morbidity of malignant cancer, a significant number of patients could be affected by the adverse reactions of using ICPis. Therefore, when ICPis are administrated, it is very important for clinicians to pay attention to one of the serious side effects – diabetes mellitus. Insulin therapy is often necessary after the diagnosis of ICPis-related diabetes, which has been proved as an effective method to prevent diabetic ketoacidosis (DKA) and other life-threatening complications in these patients.

Learning points

  • Toripalimab can cause the diabetes mellitus.

  • ICPis-related diabetes is treated primarily with insulin.

  • Immune checkpoint inhibitors cause diabetes by primarily destroying islet β cells.

  • There is not enough evidence to demonstrate that diabetic autoantibodies are related to diabetes caused by ICPis.

  • In addition to focusing on the efficacy of PD-1 inhibitor therapy, it is also necessary to pay attention to its adverse reactions, such as ICPis-related diabetes mellitus.

Background

In recent years, immune checkpoint inhibitors (ICPis) have become one of the most popular tumor immunotherapy agents. It plays an anti-tumor role by blocking immunosuppressive molecules and reactivating effector T cells to specifically kill tumor cells. However, when killing tumor cells, overactivated immune cells can lead to autoimmune damages, resulting in immune-related adverse events (IrAEs). Potential mechanisms for IrAEs induced by ICPis (1) include: the following potential ways (1) activated T cells attack normal tissues; (2) the increase of autoantibodies; and (3) the increase of inflammatory cytokines. Currently, drugs used as immunotherapy agents include programmed death-1 (PD-1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors.

ICPis were first approved to treat melanoma but have since been used to treat lung cancer, bladder cancer, blood cancers and other malignant cancers. With the increasing use of such drugs, IrAEs have been gradually increasing. Endocrine adverse reactions are one of the most common adverse reactions, mainly involving the pituitary, thyroid and pancreas and adrenal gland, causing the corresponding endocrine dysfunction. The incidence of ICPis-related diabetes was less than 1% among the patients who received the related therapy (2). In China, there is a large population of patients with malignancies (3), the use of ICPis for treating malignant cancers will be more and more frequent in local hospitals as well. Therefore, it is very important to arouse attention of the related clinicians to take urgent and correct actions to deal with the ICPis-related diabetes mellitus. Our report addressed a case of melanoma patient developed diabetes mellitus after the administration of toripalimab, providing a reference for the diagnosis and treatment of the ICPis-related serious adverse reactions, it also proved that it is very urgent and necessary to exert early monitoring of blood glucose with the administration of insulin.

Case presentation

The patient is a 20-year-old male with no history of diabetes, no history of steroids use, and BMI of 16.4. He was diagnosed with melanoma in January 2021 and subsequently had his melanoma surgically removed. After the surgery, the patient has been treated with toripalimab (3 mg/kg) every 3 weeks. After administration of the third cycle of toripalimab, he developed fasting blood glucose of 7.3 mmol/L and weight loss of about 7 kg in May 2021, without symptoms such as dry mouth, polyuria and other symptoms. Metformin and gliclazide combined with acarbose were given to regulate blood glucose after outpatient treatment in other hospital. Two months later, the fasting blood glucose measurement was 9.6 mmol/L, pre-prandial blood glucose was 14.6 mmol/L, and postprandial blood glucose at 2 h was 17.6 mmol/L. Fasting insulin value was 3.906 uIU/mL (normal range: 4.03–23.46), the 60 min value of insulin was 5.62 uIU/mL (normal range: 25–126.7), the 120 min value of insulin was 6.66 uIU/mL (normal range: 24.8–114.8). The therapeutic regimen was changed to insulin degludec–aspart (12 units twice per day) combined with acarbose. The patient’s fasting blood glucose was 20.7 mmol/L, so he was hospitalized on October 22 2021.

Investigation

The patient’s temperature was 36.6 ℃, pulse was 90 bpm, frequency of the respiratory was 20 per minute and blood pressure was 109/74 mmHg. The results of the laboratory tests are shown in Table 1. Laboratory results showed that fasting blood glucose was 9.37 mmol/L and HbA1c was 10.4%. Postprandial blood glucose was 13.43 mmol/L and 24.89 mmol/L at 1 and 2 hours, respectively, urine sugar 2+, urine ketone negative, further examination of fasting C-peptide value was 0.186 ng/mL, the 60 min value of C-peptide was 0.52 ng/mL, the 120 min value of C-peptide was 1.02 ng/mL, which was low, indicating that islet function was poor. Extended biological investigations revealed anti-glutamic acid decarboxylase antibody (GADA), insulin autoantibodies (IAA), and islet cell antibodies (ICA) were negative. Hepatic and renal function, thyroid function, sex hormone and cortisol showed no obvious abnormalities.

Table 1

Laboratory results for the patient.

Laboratory test Value Reference
Complete blood count
 White blood cell (×109/L) 4.72 3.5–9.5
 Red blood cell (×1012/L) 4.49 4.30–5.8
 Hemoglobin (g/L) 125 130–175
 Platelet (×109/L) 149 125–350
Blood biochemical
 AST (U/L) 19.6 15–40
 ALT (U/L) 22.3 9–50
 Creatinine (umol/L) 61.5 57–97
 Serum urea (mmol/L) 3.7 3.1–8.0
 Serum potassium (mmol/L) 3.57 3.5–5.3
 Serum calcium (mmol/L) 2.30 2.11–2.52
 Serum sodium (mmol/L) 141.5 137–147
 Serum chlorine (mmol/L) 106.3 99–110
Diabetes-related examination
 Blood glucose (mmol/L) 9.37 3.9–6.1
 HbA1c % 10.4 4.5–6.3
 C-peptide (ng/mL)
  Fasting 0.186 0.929–3.73
  60min 0.52 1.85–7.50
  120 min 1.02 2.78–11.1
 GADA
 ICA
 IAA
Follow-up examination
 C-peptide (ng/mL)
  Fasting 0.57 0.929–3.73
  120 min 1.01 2.78–11.1
Endocrinological examination
 ACTH (pg/mL) 33.0 7.2–63.6
 Free triiodothyronine (pg/mL) 2.56 2.0–4.4
 Free thyroxin (ng/dL) 0.98 0.93–1.70
 Thyroid-stimulating hormone (uIU/mL) 1.70 0.27–4.20
 Antithyroglobulin antibody (IU/mL) 19.50 0–115
 Thyroid microparticle antibody (IU/mL) 23.10 0–32
 Trans triiodothyronine (ng/mL) 0.638 0.31–0.95
 Luteinizing hormone (mIU/mL) 10.9 ≤8.6
 Follicle-stimulating hormone (mIU/mL) 34.5 ≤12.4
 Prolactin (ng/mL) 20.20 2.1–17.7
 Testosterone (ng/dL) 633 241–827
 Estradiol (pg/mL) 25.0 25.8–60.7
 Progesterone (ng/mL) 0.12 <0.05–0.149
 Cortisol (µg/L) 197.30 57.2–194
Urine analysis
 Urinary occult blood test
 Urinary glucose 2+
 Urinary ketone

ALT, alanine transaminase; AST, aspartate aminotransferase; GADA, glutamate decarboxylase autoantibody; HbA1c, hemoglobin A1c; IAA, anti-insulin autoantibodies; ICA, islet cell antibodies.

Treatment

For treatment, we temporarily administrated insulin pump (basal rate: 0.4 units per hour and preprandial dose: 5 units), and dynamically monitored blood glucose for 24 h. After proper blood glucose control during hospitalization, he was discharged on November 1 2021. The treatment regimen at discharge was subcutaneous injection of insulin aspartic (8 units, three times a day) and insulin degludec (16 units, once a night) combined with acarbose treatment.

Outcome and follow-up

The patient was re-examined in the outpatient department of our hospital after 1 year. The patient did not use toripalimab after discharge, and there was no recurrence of melanoma. Laboratory results showed that fasting blood glucose was 10.4 mmol/L and HbA1c was 8.6%. Postprandial blood glucose was 15.2 mmol/L at 2 h, GADA was still negative, and thyroid function and cortisol showed no obvious abnormalities. The fasting C-peptide value was 0.57 ng/mL and the 120 min value of C-peptide was 1.01 ng/mL, suggesting that the C-peptide function had not recovered. Because the patient did not have strict diet control, his blood glucose was still poorly controlled, and the patient was informed to change the treatment regimen to subcutaneously inject insulin aspartic (10 units in the morning, 9 units at noon and 9 units at night) and insulin degludec (18 units, once every night), and the patient's diabetes education was strengthened.

Discussion

Diabetes mellitus caused by immune-related inhibitors is relatively rare, with an incidence of less than 1%, mostly in patients treated with PD-1 inhibitors or PD-L1 inhibitors. It usually occurs within a few weeks to 1 year after drug use, with an average onset of about 20 weeks (2). However, due to the high incidence of malignant cancer in China and the large number of patients, clinicians should be aware of the adverse reactions associated with ICPis.

This patient had normal blood glucose and no family history of diabetes before the treatment with toripalimab. After administration of the third cycle of PD-1 inhibitor, the fasting blood glucose increased, type 2 diabetes mellitus was considered in the other hospital, and oral hypoglycemic drugs were given, but blood glucose still increased rapidly. After treatment at our hospital, we considered that the patient was 20 years old, had no family history of diabetes, no symptoms of ketoacidosis onset, was negative for all islet-related antibodies, and had the history of PD-1 medication. Therefore, the patient was considered not to be typical type 2 diabetes mellitus. The patient’s pituitary hormones, cortisol, adrenal corticosteroids, thyroid hormones and other glucocorticoids were normal, and the diabetes-related antibodies were all negative. The possibility of increased blood glucose caused by endocrine diseases can also be ruled out. According to WHO Diabetes Classification in 2019, diabetes caused by immune checkpoint inhibitors should be classified as a special type of diabetes (drug- or chemical-induced). Although the details remain unclear, the main mechanism of diabetes in these patients is the destruction of pancreatic beta cells by enhanced T-lymphocyte activity, resulting in absolute insulin deficiency, which is basically consistent with type 1 diabetes and more similar to acute-onset type 1 diabetes. Therefore, most literature currently treats this type of diabetes as type 1 diabetes.

PD-1 is a cell-surface receptor that inhibits the inflammatory activity of T cells and is often expressed in patients’ T cells. Under normal circumstances, T cells exert immune effects through stimulation of coupled signals, so that the body’s immune activation and immunosuppression are in a state of balance. When T cells are activated, PD-1 expression is provoked, and PD-L1 or PD-L2 is combined with ligands to inhibit the activation of T lymphocytes, regulate the contact between T-lymphocytes and antigen-presenting cells or effector cells, and promotes the proliferation of immunosuppressive cells-regulatory T cells (Treg), thereby inhibiting the immune effect of the body (4). In the process of tumor occurrence and development, immune escape is an important process, in which tumor cells escape the immune surveillance of the body through various mechanisms. Chen et al. (5) showed that tumor cells promote tumor immune escape by regulating PD-1/PD-L1 signaling pathway. Therefore, the anti-tumor mechanism of PD-1 inhibitors is to restore the immune surveillance function of tumor cells by inhibiting the PD-1/PD-L1 pathway to limit the immune escape of tumor cells.

The exact mechanism by which treatment with the PD-1 inhibitor toripalimab causes diabetes is not fully understood. Stamatouli et al. (2) showed that ICPis can destroy the islet cells of mice within days to weeks and found that the glucagon level of the diabetic patient did not decrease randomly, indicating that the target cells of damage were islet β cells, while α cells were not affected. This may be due to the fact that PD-1 inhibitors block the binding of PD-L1 on islet β cells to the PD-1 receptor of autoreactive T cells, resulting in a disinhibitory effect on autoreactive T cells, thus damaging islet β cells.

Diabetes caused by PD-1 inhibitors treatment has the following important characteristics: (1) rapid increase of blood glucose, rapid onset and rapid progression, and the incidence of ketoacidosis is as high as 59%–71%; (2) endogenous insulin deficiency progresses rapidly, and the c-peptide level in most patients is low, rapidly and continuously decreased or even undetectable; and (3) the risk of diabetic ketoacidosis (DKA) is higher if insulin is not detected and treated in time (2). In this case, because we realized that the abnormal blood glucose in this patient was drug-related and insulin was administered promptly. DKA did not occur when fasting blood glucose increased to 20.7 mmol/L.

For patients with negative GADA, ICA, and IAA, there is not enough evidence to demonstrate that diabetic autoantibodies are related to diabetes caused by ICPis. Stamatouli et al. (2) reported that among 27 ICPis-related diabetes patients, only 40% showed positive autoantibodies. Ansari MJ et al. (6) observed that in NOD mice that blocked PD-1 and PD-L1, there was no correlation between the level of islet autoantibody and the occurrence of diabetes. In addition, antibodies are not used as a basis for diagnosis in the diagnostic criteria of ICPis-related diabetes. Nevertheless, studies have shown that, compared with the patients with negative autoantibodies, those with ICPis-related diabetes and positive antibodies have a shorter onset time and a higher frequency of DKA. Based on the above, it informed that islet autoantibodies cannot be used as a basis for diagnosis but can be used as a screening indicator.

As for the treatment of ICPis-related diabetes, Barroso-Sousa R et al. pointed out that as the main sign of this type of diabetes is insulin deficiency, insulin treatment should be started once the diagnosis is made (7), and insulin treatment is also suggested when diabetes is difficult to classify. A typical insulin regimen includes basal insulin (e.g., insulin detemir, insulin degludec, or insulin glargine) plus bolus insulin (e.g., insulin lispro, insulin aspart, or insulin glulisine). With the help of the diabetologist, an insulin pump could be initiated if appropriate. At the same time, the existence of DKA needs to be assessed and further treatment is conducted according to common terminology criteria for adverse events (CTARE) (8).

PD-1 inhibitors not only affect islet β cells, but also damage other endocrine gland, such as thyroid, pituitary, adrenal gland, resulting in the dysfunction of related glands. The incidence of thyroid dysfunction caused by PD-1 inhibitor therapy is about 5%–10%, and normally occurs 2–6 weeks after the start of treatment. The incidence of pituitary inflammation induced by PD-1 inhibitor is only 0.4%, and the onset time is usually 3–5 months (9). Adrenocortical hypofunction usually appears after several months of PD-1 inhibitor monotherapy. When the patient was admitted to the hospital for treatment, we examined his thyroid function, pituitary hormones, cortisol, and adrenal corticosteroids and found no obvious abnormalities, indicating that the patient has no damage to the thyroid, pituitary, and adrenal glands. However, further follow-up is still needed to determine whether these glands will be abnormal in the future. The Society for Immunotherapy of Cancer (SITC) (10) recommended that all patients should have serum glucose, glycated hemoglobin, ACTH, cortisol, and thyroid function tested before ICPis therapy, and monthly follow-up for the first 6 months, then every 3 months for the next 6 months and every 6 months for rest of 1 year. Therefore, after discharge, the patients were instructed to pay attention to their symptoms and to follow up the above indicators regularly.

In conclusion, based on this case report it is expected that oncologists and endocrinologists can improve the understanding of this disease. In addition to focusing on the efficacy of PD-1 inhibitor therapy, it is also necessary to pay attention to its adverse reactions. Based on the large population of malignant cancer patients in China, we need to be vigilant in patients using ICPis, strengthen patient education, and follow-up regularly to avoid life-threatening adverse reactions such as DKA and adrenal crisis.

Declaration of interest

The authors declare that there is no duality of interest associated with this manuscript.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent was obtained from the patient for publication of the submitted article.

Author contribution statement

W Zhang wrote the initial draft of the manuscript, and W Xu contributed to the discussion. All authors critically reviewed the manuscript and approved the final version of the manuscript.

References

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  • 2

    Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H, Weiss SA, Gettinger S, Sznol M, Young A, Rushakoff R, et al.Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes 2018 67 14711480. (https://doi.org/10.2337/dbi18-0002)

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  • 3

    Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, & He J. Cancer statistics in China, 2015. CA: a Cancer Journal for Clinicians 2016 66 115132. (https://doi.org/10.3322/caac.21338)

    • PubMed
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  • 4

    Adler AS, Mizrahi RA, Spindler MJ, Adams MS, Asensio MA, Edgar RC, Leong J, Leong R, & Johnson DS. Rare, high-affinity mouse anti-PD-1 antibodies that function in checkpoint blockade, discovered using microfluidics and molecular genomics. mAbs 2017 9 12701281. (https://doi.org/10.1080/19420862.2017.1371386)

    • PubMed
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  • 5

    Chen L, Heymach JV, Qin FX, & Gibbons DL. The mutually regulatory loop of epithelial-mesenchymal transition and immunosuppression in cancer progression. Oncoimmunology 2015 4 e1002731. (https://doi.org/10.1080/2162402X.2014.1002731)

    • PubMed
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    • Export Citation
  • 6

    Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, et al.The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. Journal of Experimental Medicine 2003 198 6369. (https://doi.org/10.1084/jem.20022125)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Barroso-Sousa R, Ott PA, Hodi FS, Kaiser UB, Tolaney SM, & Min L. Endocrine dysfunction induced by immune checkpoint inhibitors: practical recommendations for diagnosis and clinical management. Cancer 2018 124 11111121. (https://doi.org/10.1002/cncr.31200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Ruggeri RM, Campennì A, Giuffrida G, Trimboli P, Giovanella L, Trimarchi F, & Cannavò S. Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know). Journal of Endocrinological Investigation 2019 42 745756. (https://doi.org/10.1007/s40618-018-0984-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Faje AT, Sullivan R, Lawrence D, Tritos NA, Fadden R, Klibanski A, & Nachtigall L. Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. Journal of Clinical Endocrinology and Metabolism 2014 99 40784085. (https://doi.org/10.1210/jc.2014-2306)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, et al.Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. Journal for ImmunoTherapy of Cancer 2017 5 95. (https://doi.org/10.1186/s40425-017-0300-z)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

  • Collapse
  • Expand
  • 1

    Kennedy LB, & Salama AKS. A review of cancer immunotherapy toxicity. CA: a Cancer Journal for Clinicians 2020 70 86104. (https://doi.org/10.3322/caac.21596)

  • 2

    Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H, Weiss SA, Gettinger S, Sznol M, Young A, Rushakoff R, et al.Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes 2018 67 14711480. (https://doi.org/10.2337/dbi18-0002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, & He J. Cancer statistics in China, 2015. CA: a Cancer Journal for Clinicians 2016 66 115132. (https://doi.org/10.3322/caac.21338)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Adler AS, Mizrahi RA, Spindler MJ, Adams MS, Asensio MA, Edgar RC, Leong J, Leong R, & Johnson DS. Rare, high-affinity mouse anti-PD-1 antibodies that function in checkpoint blockade, discovered using microfluidics and molecular genomics. mAbs 2017 9 12701281. (https://doi.org/10.1080/19420862.2017.1371386)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Chen L, Heymach JV, Qin FX, & Gibbons DL. The mutually regulatory loop of epithelial-mesenchymal transition and immunosuppression in cancer progression. Oncoimmunology 2015 4 e1002731. (https://doi.org/10.1080/2162402X.2014.1002731)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, et al.The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. Journal of Experimental Medicine 2003 198 6369. (https://doi.org/10.1084/jem.20022125)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Barroso-Sousa R, Ott PA, Hodi FS, Kaiser UB, Tolaney SM, & Min L. Endocrine dysfunction induced by immune checkpoint inhibitors: practical recommendations for diagnosis and clinical management. Cancer 2018 124 11111121. (https://doi.org/10.1002/cncr.31200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Ruggeri RM, Campennì A, Giuffrida G, Trimboli P, Giovanella L, Trimarchi F, & Cannavò S. Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know). Journal of Endocrinological Investigation 2019 42 745756. (https://doi.org/10.1007/s40618-018-0984-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Faje AT, Sullivan R, Lawrence D, Tritos NA, Fadden R, Klibanski A, & Nachtigall L. Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. Journal of Clinical Endocrinology and Metabolism 2014 99 40784085. (https://doi.org/10.1210/jc.2014-2306)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, et al.Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. Journal for ImmunoTherapy of Cancer 2017 5 95. (https://doi.org/10.1186/s40425-017-0300-z)

    • PubMed
    • Search Google Scholar
    • Export Citation