|
1
|
Arecco A, Petolicchio C, Pastorino A, Tanda ET, Vera L, Boschetti M, Cocchiara F, Maggi DC, Ferone D, Gatto F. Cemiplimab and diabetic ketoacidosis: a case report of a rare endocrinopathy associated with immune checkpoint inhibitors. Front Endocrinol (Lausanne) 2025; 16:1550702. [PMID: 40201762 PMCID: PMC11975561 DOI: 10.3389/fendo.2025.1550702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 03/07/2025] [Indexed: 04/10/2025] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) have revolutionised the cancer treatment landscape in the last decades, improving the outcome of several tumours, such as cutaneous squamous cell carcinoma (cSCC). ICIs are antibodies blocking several immune checkpoint pathways, as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) with its ligand PD-L1. However, the activation of immune response can cause a broad range of side effects, called immune-related adverse events (irAEs). Endocrine irAEs are mainly represented by thyroid dysfunctions (thyrotoxicosis or hypothyroidism) and hypophysitis, while adrenal insufficiency and diabetes mellitus (DM) are less common. Diabetic ketoacidosis (DKA) is a potential life-threatening presentation of ICI-induced insulin-dependent DM (IDDM). This report presents a rare case of DKA and IDDM secondary to anti-PD-1 antibody cemiplimab therapy, and this is the third described in the literature to date. Case presentation We describe the case of a 62-year-old female patient with metastatic perianal squamous cell carcinoma who developed DKA and IDDM after the fifth cycle of cemiplimab. Hyperglycemia (1187 mg/dL), metabolic acidosis (pH 7.27) with bicarbonate levels of 11.9 mmol/L, arterial partial pressure of carbon dioxide of 25.7 mmHg with increased anion gap (equal to 25), and hyperketonuria were present. Adequate glycaemic control was difficult to maintain, and intravenously therapy (insulin, sodium bicarbonate, potassium, and fluids) was required for a long time. Subcutaneous basal-bolus insulin treatment was started, but glycaemic control was scarce, also due to the concomitant administration of prednisone for immune-related hepatotoxicity, until the subject's death. Conclusion This report underlines the importance of the awareness on endocrine irAEs with ICIs, particularly life-threatening DKA. A baseline assessment of glycemia and glycated hemoglobin is mandatory, and we recommend a close monitoring of glycemic trend over time during ICIs therapy. Patients and their caregivers should be informed and counselled to recognise DKA signs and symptoms.
Collapse
Affiliation(s)
- Anna Arecco
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
| | - Cristian Petolicchio
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
| | | | - Enrica Teresa Tanda
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova, Italy
- Medical Oncology 2, IRCCS Policlinico San Martino, Genova, Italy
| | - Lara Vera
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Mara Boschetti
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | | | - Davide Carlo Maggi
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Diego Ferone
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Federico Gatto
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| |
Collapse
|
|
2
|
Yang B, Chi Q, Li X, Wang J. Prediction of traditional Chinese medicine for diabetes based on the multi-source ensemble method. Front Pharmacol 2025; 16:1454029. [PMID: 39950110 PMCID: PMC11822566 DOI: 10.3389/fphar.2025.1454029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 01/03/2025] [Indexed: 02/16/2025] Open
Abstract
Introduction Traditional Chinese medicine (TCM) prescriptions are generally formulated by experienced TCM researchers based on their expertise and data statistical methods. Methods In order to predict TCM formulas for diabetes more accurately, this paper proposes a novel multi-source ensemble prediction method that combines machine learning ensemble techniques and multi-source data. In this method, the multi-source data contain datasets based on the components and targets (DPP-4 and GLP-1). Gradient boosting decision tree (GBDT), flexible neural tree (FNT), and Light Gradient Boosting Machine (LightGBM) algorithms are trained using these two types of datasets, respectively. The compound dataset from the TCMSP database is then used as testing data to predict and screen the active ingredients. The frequencies of occurrences of medicinal herbs corresponding to these three algorithms are obtained, each containing an active ingredient list. Finally, the frequencies of occurrences of the medicinal herbs obtained from the three algorithms using the component and target datasets are integrated to select duplicate drugs as the candidate drugs for diabetes treatment. Results The identification results reveal that theproposed ensemble method has higher accuracy than GBDT, FNT, and LightGBM. The medicinal herbs predicted include Lycii fructus, Amygdalus communis vas, Chrysanthemi flos, Hippophae fructus, Mori folium, Croci stigma, Maydis stigma, Ephedrae herba, Cimicifugae rhizoma, licorice, and Epimedii herba, all of which have been proven effective in the treatment of diabetes. Discussions The results of network pharmacology show that myrrha can play a role in treating diabetes through multiple targets and pathways.
Collapse
Affiliation(s)
- Bin Yang
- School of Information Science and Engineering, Zaozhuang University, Zaozhuang, China
| | - Qingyun Chi
- School of Information Science and Engineering, Zaozhuang University, Zaozhuang, China
| | - Xiang Li
- Information Department, Qingdao Eighth People’s Hospital, Qingdao, China
| | - Jinglong Wang
- College of Food Science and Pharmaceutical Engineering, Zaozhuang University, Zaozhuang, China
| |
Collapse
|
|
3
|
Zhan M, Long Q, He J, Huang L, Wu B, Xu H, Mo L, Xu T. Immune checkpoint inhibitor-induced diabetes mellitus: clinical characteristics and risk factors. Front Immunol 2025; 16:1499074. [PMID: 39925806 PMCID: PMC11802519 DOI: 10.3389/fimmu.2025.1499074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 01/09/2025] [Indexed: 02/11/2025] Open
Abstract
Background Emerging evidence indicates that immune checkpoint inhibitor-induced diabetes mellitus (ICI-DM) might be more common than initially reported, and more different clinical pictures associated with ICI-DM were described. Objective The aim of our study was to identify the clinical characteristics and possible predictive factors of ICI-DM. Methods We conducted a retrospective review of patients who received immune checkpoint inhibitors (ICI) at West China Hospital, Sichuan University until June 2023. Patients were reviewed at death or on 7 May 2024. We applied logistic regression to study the associations between clinical characteristics and ICI-DM. Results Our study included 8,199 participants who received ICI between October 2014 and June 2023. Among them, 1,077 patients (13.14%) developed ICI-DM according to diagnostic criteria based on guidelines. By excluding patients influenced by glucocorticoids or immunosuppressants, ICI-DM was observed in 713 of 8,199 (8.70%) patients. In all patients, hypertension, hyperlipidemia, using glucocorticoids or immunosuppressants, lung cancer, and using more than one pathway of ICI were associated with a higher risk of ICI-DM. However, the risk factors for ICI-DM in patients without the influence of glucocorticoids or immunosuppressants were only hypertension, hyperlipidemia, and pancreatic lesions. In all patients and those patients without the influence of glucocorticoids and immunosuppressants, hypertension and hyperlipidemia may increase the risk for ICI-DM. Conclusions This large, real-world cohort demonstrates that the incidence of ICI-DM may be underestimated in previous literature. Blood glucose monitoring is needed in patients receiving ICI therapy. Clinical trial registration https://www.chictr.org.cn, identifier ChiCTR2300075974.
Collapse
Affiliation(s)
- Mei Zhan
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Qinran Long
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Jinhan He
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Litao Huang
- Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, China
| | - Bin Wu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Haixia Xu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Li Mo
- Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Xu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
4
|
Dökmetaş M, Muğlu H, Özcan E, Bayram Kuvvet B, Helvacı K, Kalacı E, Kahraman S, Aykan MB, Çiçin İ, Selçukbiricik F, Ölmez ÖF, Bilici A. Endocrine Adverse Events in Patients Treated with Immune Checkpoint Inhibitors: A Comprehensive Analysis. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:123. [PMID: 39859105 PMCID: PMC11766766 DOI: 10.3390/medicina61010123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 01/06/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025]
Abstract
Background and Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but their use is associated with a spectrum of immune-related adverse events (irAEs), including endocrine disorders. This study aims to investigate the incidence, timing, treatment modalities, and impact of ICI-related endocrine side effects in cancer patients. Materials and Methods: This retrospective study analyzed 139 cancer patients treated with ICIs between 2016 and 2022. Data regarding endocrine irAEs, including hypothyroidism, hyperthyroidism, hypophysitis, and diabetes mellitus, were collected. The study examined the timing of irAE onset, management approaches, and the association between irAEs and treatment outcomes. Results: The most common endocrine irAE was hypothyroidism (65.5%), followed by hyperthyroidism (2.3%), hypophysitis (8.6%), and diabetes mellitus (0.7%). These disorders typically emerged within the first six months of ICI therapy. Most cases were managed conservatively or with hormone replacement therapy. Patients who developed endocrine irAEs exhibited a higher objective response rate (ORR) and clinical benefit rate (CBR) compared to those without irAEs. Conclusions: Endocrine dysfunction is a significant toxicity of ICI therapy. Early recognition, prompt diagnosis, and appropriate management are crucial to minimize their impact on patient health and quality of life. This study highlights the potential association between irAEs and improved clinical outcomes. Further research is needed to elucidate the underlying mechanisms and identify predictive biomarkers for irAE development.
Collapse
Affiliation(s)
- Meriç Dökmetaş
- Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul 34810, Turkey; (M.D.); (Ö.F.Ö.); (A.B.)
| | - Harun Muğlu
- Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul 34810, Turkey; (M.D.); (Ö.F.Ö.); (A.B.)
| | - Erkan Özcan
- Department of Medical Oncology, Faculty of Medicine, Trakya University, Edirne 22030, Turkey;
| | - Buket Bayram Kuvvet
- Department of Medical Oncology, Faculty of Medicine, Koç University, Istanbul 34450, Turkey; (B.B.K.); (F.S.)
| | - Kaan Helvacı
- Department of Medical Oncology, Memorial Hospital, Ankara 06520, Turkey;
| | - Ender Kalacı
- Department of Medical Oncology, Faculty of Medicine, Ankara University, Ankara 06620, Turkey;
| | - Seda Kahraman
- Department of Medical Oncology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara Bilkent City Hospital, Ankara 06800, Turkey;
| | - Musa Barış Aykan
- Department of Medical Oncology, Gülhane Training and Research Hospital, University of Health Sciences, Ankara 06010, Turkey;
| | - İrfan Çiçin
- Department of Medical Oncology, Faculty of Medicine, Istinye University, Istanbul 34010, Turkey;
| | - Fatih Selçukbiricik
- Department of Medical Oncology, Faculty of Medicine, Koç University, Istanbul 34450, Turkey; (B.B.K.); (F.S.)
| | - Ömer Fatih Ölmez
- Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul 34810, Turkey; (M.D.); (Ö.F.Ö.); (A.B.)
| | - Ahmet Bilici
- Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul 34810, Turkey; (M.D.); (Ö.F.Ö.); (A.B.)
| |
Collapse
|
|
5
|
Daetwyler E, Zippelius A, Danioth S, Donath MY, Gut L. Nivolumab-induced diabetes mellitus-a case report with literature review of the treatment options. Front Immunol 2023; 14:1248919. [PMID: 37965350 PMCID: PMC10640970 DOI: 10.3389/fimmu.2023.1248919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/10/2023] [Indexed: 11/16/2023] Open
Abstract
Background Immune checkpoint inhibitor (ICI) treatment has become important for treating various cancer types, including metastatic renal cell carcinoma. However, ICI treatment can lead to endocrine immune-related adverse events (irAEs) by overstimulating the patient's immune system. Here, we report a rare case of a new onset of diabetes mellitus (DM), caused by nivolumab, and we discuss the feasible treatment options with a focus on TNF antagonism. Case presentation A 50-year-old man was diagnosed with metastatic renal cell carcinoma. Due to systemic progression, a combined immunotherapy with ipilimumab and nivolumab was initiated, according to the current study protocol (SAKK 07/17). The administration of ipilimumab was stopped after 10 months, due to partial response as seen in the computer tomography (CT), and nivolumab was continued as monotherapy. Fourteen months after the start of the treatment, the patient was admitted to the emergency department with lethargy, vomiting, blurred vision, polydipsia, and polyuria. The diagnosis of DM with diabetic ketoacidosis was established, although autoantibodies to β-cells were not detectable. Intravenous fluids and insulin infusion treatment were immediately initiated with switching to a subcutaneous administration after 1 day. In addition, the patient received an infusion of the TNF inhibitor infliximab 4 days and 2 weeks after the initial diagnosis of DM. However, the C-peptide values remained low, indicating a sustained insulin deficiency, and the patient remained on basal bolus insulin treatment. Two months later, nivolumab treatment was restarted without destabilization of the diabetic situation. Conclusions In contrast to the treatment of other irAEs, the administration of corticosteroids is not recommended in ICI-induced DM. The options for further treatment are mainly based on the low numbers of case series and case reports. In our case, the administration of infliximab-in an attempt to salvage the function of β-cells-was not successful, and this is in contrast to some previous reports. This apparent discrepancy may be explained by the absence of insulin resistance in our case. There is so far no evidence for immunosuppressive treatment in this situation. Prompt recognition and immediate start of insulin treatment are most important in its management.
Collapse
Affiliation(s)
- Eveline Daetwyler
- Department of Medical Oncology, University Hospital Basel, Basel, Switzerland
| | - Alfred Zippelius
- Department of Medical Oncology, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Simona Danioth
- Clinic for Endocrinology, Diabetes & Metabolism, Luzern Cantonal Hospital, Luzern, Switzerland
| | - Marc Y. Donath
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinic for Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland
| | - Lara Gut
- Clinic for Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland
- Clinic for Endocrinology & Diabetes, Medical University Clinic Baselland, Liestal, Switzerland
| |
Collapse
|
|
6
|
Wu L, Tsang V, Menzies AM, Sasson SC, Carlino MS, Brown DA, Clifton-Bligh R, Gunton JE. Risk Factors and Characteristics of Checkpoint Inhibitor-Associated Autoimmune Diabetes Mellitus (CIADM): A Systematic Review and Delineation From Type 1 Diabetes. Diabetes Care 2023; 46:1292-1299. [PMID: 37220262 DOI: 10.2337/dc22-2202] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 03/27/2023] [Indexed: 05/25/2023]
Abstract
BACKGROUND Checkpoint inhibitor-associated autoimmune diabetes mellitus (CIADM) is a distinct form of autoimmune diabetes that is a rare complication of immune checkpoint inhibitor therapy. Data regarding CIADM are limited. PURPOSE To systematically review available evidence to identify presentation characteristics and risk factors for early or severe presentations of adult patients with CIADM. DATA SOURCES MEDLINE and PubMed databases were reviewed. STUDY SELECTION English full text articles from 2014 to April 2022 were identified with a predefined search strategy. Patients meeting diagnostic criteria for CIADM with evidence of hyperglycemia (blood glucose level >11 mmol/L or HbA1c ≥6.5%) and insulin deficiency (C-peptide <0.4 nmol/L and/or diabetic ketoacidosis [DKA]) were included for analysis. DATA EXTRACTION With the search strategy we identified 1,206 articles. From 146 articles, 278 patients were labeled with "CIADM," with 192 patients meeting our diagnostic criteria and included in analysis. DATA SYNTHESIS Mean ± SD age was 63.4 ± 12.4 years. All but one patient (99.5%) had prior exposure to either anti-PD1 or anti-PD-L1 therapy. Of the 91 patients tested (47.3%), 59.3% had susceptibility haplotypes for type 1 diabetes (T1D). Median time to CIADM onset was 12 weeks (interquartile range 6-24). DKA occurred in 69.7%, and initial C-peptide was low in 91.6%. T1D autoantibodies were present in 40.4% (73 of 179) and were significantly associated with DKA (P = 0.0009) and earlier time to CIADM onset (P = 0.02). LIMITATIONS Reporting of follow-up data, lipase, and HLA haplotyping was limited. CONCLUSIONS CIADM commonly presents in DKA. While T1D autoantibodies are only positive in 40.4%, they associate with earlier, more severe presentations.
Collapse
Affiliation(s)
- Linda Wu
- The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- University of Sydney, Sydney, New South Wales, Australia
- Royal North Shore Hospital, Sydney, New South Wales, Australia Sydney, New South Wales, Australia
- Westmead Hospital, Sydney, New South Wales, Australia
| | - Venessa Tsang
- University of Sydney, Sydney, New South Wales, Australia
- Royal North Shore Hospital, Sydney, New South Wales, Australia Sydney, New South Wales, Australia
| | - Alexander M Menzies
- University of Sydney, Sydney, New South Wales, Australia
- Royal North Shore Hospital, Sydney, New South Wales, Australia Sydney, New South Wales, Australia
- Melanoma Institute Australia, Sydney, New South Wales, Australia
- Mater Hospital, Sydney, New South Wales, Australia
| | - Sarah C Sasson
- University of Sydney, Sydney, New South Wales, Australia
- Westmead Hospital, Sydney, New South Wales, Australia
- Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Sydney, New South Wales, Australia
| | - Matteo S Carlino
- University of Sydney, Sydney, New South Wales, Australia
- Westmead Hospital, Sydney, New South Wales, Australia
- Melanoma Institute Australia, Sydney, New South Wales, Australia
- Mater Hospital, Sydney, New South Wales, Australia
| | - David A Brown
- The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- University of Sydney, Sydney, New South Wales, Australia
- Westmead Hospital, Sydney, New South Wales, Australia
- Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Sydney, New South Wales, Australia
| | - Roderick Clifton-Bligh
- University of Sydney, Sydney, New South Wales, Australia
- Royal North Shore Hospital, Sydney, New South Wales, Australia Sydney, New South Wales, Australia
| | - Jenny E Gunton
- The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- University of Sydney, Sydney, New South Wales, Australia
- Westmead Hospital, Sydney, New South Wales, Australia
| |
Collapse
|
|
7
|
Cardona Z, Sosman JA, Chandra S, Huang W. Endocrine side effects of immune checkpoint inhibitors. Front Endocrinol (Lausanne) 2023; 14:1157805. [PMID: 37251665 PMCID: PMC10210589 DOI: 10.3389/fendo.2023.1157805] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/05/2023] [Indexed: 05/31/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have increasingly been the mainstay of treatment for numerous malignancies. However, due to their association with autoimmunity, ICIs have resulted in a variety of side effects that involve multiple organs including the endocrine system. In this review article, we describe our current understanding of the autoimmune endocrinopathies as a result of the use of ICIs. We will review the epidemiology, pathophysiology, clinical presentation, diagnosis, and management of the most commonly encountered endocrinopathies, including thyroiditis, hypophysitis, Type 1 diabetes, adrenalitis, and central diabetes insipidus.
Collapse
Affiliation(s)
- Zulma Cardona
- Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Jeffrey A. Sosman
- Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Sunandana Chandra
- Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Wenyu Huang
- Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| |
Collapse
|
|
8
|
Xiong P, Zhang F, Liu F, Zhao J, Huang X, Luo D, Guo J. Metaflammation in glucolipid metabolic disorders: Pathogenesis and treatment. Biomed Pharmacother 2023; 161:114545. [PMID: 36948135 DOI: 10.1016/j.biopha.2023.114545] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/11/2023] [Accepted: 03/14/2023] [Indexed: 03/22/2023] Open
Abstract
The public health issue of glucolipid metabolic disorders (GLMD) has grown significantly, posing a grave threat to human wellness. Its prevalence is rising yearly and tends to affect younger people. Metaflammation is an important mechanism regulating body metabolism. Through a complicated multi-organ crosstalk network involving numerous signaling pathways such as NLRP3/caspase-1/IL-1, NF-B, p38 MAPK, IL-6/STAT3, and PI3K/AKT, it influences systemic metabolic regulation. Numerous inflammatory mediators are essential for preserving metabolic balance, but more research is needed to determine how they contribute to the co-morbidities of numerous metabolic diseases. Whether controlling the inflammatory response can influence the progression of GLMD determines the therapeutic strategy for such diseases. This review thoroughly examines the role of metaflammation in GLMD and combs the research progress of related therapeutic approaches, including inflammatory factor-targeting drugs, traditional Chinese medicine (TCM), and exercise therapy. Multiple metabolic diseases, including diabetes, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and others, respond therapeutically to anti-inflammatory therapy on the whole. Moreover, we emphasize the value and open question of anti-inflammatory-based means for treating GLMD.
Collapse
Affiliation(s)
- Pingjie Xiong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| | - Fan Zhang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| | - Fang Liu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| | - Jiayu Zhao
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| | - Xiaoqiang Huang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China.
| | - Duosheng Luo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| |
Collapse
|
|
9
|
Okubo M, Hataya Y, Fujimoto K, Iwakura T, Matsuoka N. Recovery from insulin dependence in immune checkpoint inhibitor-associated diabetes mellitus: A case report. J Diabetes Investig 2022; 14:147-150. [PMID: 36251515 PMCID: PMC9807149 DOI: 10.1111/jdi.13927] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/15/2022] [Accepted: 09/27/2022] [Indexed: 01/07/2023] Open
Abstract
Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare immune-related adverse event and is usually considered permanent. Here, we report the first case of a 54-year-old man with ICI-DM who recovered from insulin dependence. He was diagnosed with lung cancer and started pembrolizumab therapy. After seven cycles, he developed ICI-associated secondary adrenal insufficiency and started hydrocortisone supplementation. Subsequently, he complained of fatigue, and blood examinations showed hyperglycemia with ketosis. A glucagon challenge test indicated insulin dependence. He was diagnosed with ICI-DM and insulin therapy was initiated. Pembrolizumab therapy was discontinued due to concomitant ICI-associated hepatitis. Six months later, a glucagon challenge test result showed an improvement in insulin secretion, and insulin therapy was discontinued. The lung cancer lesions continued to shrink. Even if ICI-DM develops, it might be possible to control the underlying cancer while avoiding lifelong insulin therapy through early discontinuation of ICI.
Collapse
Affiliation(s)
- Marie Okubo
- Department of Diabetes and EndocrinologyKobe City Medical Center General HospitalKobeJapan
| | - Yuji Hataya
- Department of Diabetes and EndocrinologyKobe City Medical Center General HospitalKobeJapan
| | - Kanta Fujimoto
- Department of Diabetes and EndocrinologyKobe City Medical Center General HospitalKobeJapan
| | - Toshio Iwakura
- Department of Diabetes and EndocrinologyKobe City Medical Center General HospitalKobeJapan
| | - Naoki Matsuoka
- Department of Diabetes and EndocrinologyKobe City Medical Center General HospitalKobeJapan
| |
Collapse
|
|
10
|
Muniz TP, Araujo DV, Savage KJ, Cheng T, Saha M, Song X, Gill S, Monzon JG, Grenier D, Genta S, Allen MJ, Arteaga DP, Saibil SD, Butler MO, Spreafico A, Hogg D. CANDIED: A Pan-Canadian Cohort of Immune Checkpoint Inhibitor-Induced Insulin-Dependent Diabetes Mellitus. Cancers (Basel) 2021; 14:cancers14010089. [PMID: 35008256 PMCID: PMC8750429 DOI: 10.3390/cancers14010089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/17/2021] [Accepted: 12/21/2021] [Indexed: 01/08/2023] Open
Abstract
Simple Summary Immune checkpoint inhibitor-induced insulin-dependent diabetes mellitus (ICI-induced IDDM) is an emerging form of autoimmune diabetes. We describe the characteristics of 34 patients who developed ICI-induced IDDM across five Canadian cancer centres. We observed that presentation with hyperglycemic crisis is common and that patients treated with combination immunotherapy regimens develop ICI-induced IDDM earlier than those treated with monotherapy. Our results suggest that ICI-induced IDDM is irreversible but is associated with high tumor response rates and prolonged survival. The data generated by this study may help clinicians manage ICI-induced IDDM. Abstract Immune checkpoint inhibitor (ICI)-induced insulin-dependent diabetes mellitus (IDDM) is a rare but potentially fatal immune-related adverse event (irAE). In this multicentre retrospective cohort study, we describe the characteristics of ICI-induced IDDM in patients treated across five Canadian cancer centres, as well as their tumor response rates and survival. In 34 patients identified, 25 (74%) were male and 19 (56%) had melanoma. All patients received anti-programed death 1 (anti-PD1) or anti-programmed death ligand-1 (anti-PD-L1)-based therapy. From ICI initiation, median time to onset of IDDM was 2.4 months (95% CI 1.1–3.6). Patients treated with anti-PD1/PD-L1 in combination with an anti-cytotoxic T lymphocyte antigen 4 antibody developed IDDM earlier compared with patients on monotherapy (1.4 vs. 3.9 months, p = 0.05). Diabetic ketoacidosis occurred in 21 (62%) patients. Amongst 30 patients evaluable for response, 10 (33%) had a complete response and another 10 (33%) had a partial response. Median overall survival was not reached (95% CI NE; median follow-up 31.7 months). All patients remained insulin-dependent at the end of follow-up. We observed that ICI-induced IDDM is an irreversible irAE and may be associated with a high response rate and prolonged survival.
Collapse
Affiliation(s)
- Thiago P. Muniz
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, University Health Network, Toronto, ON M5S 1Z5, Canada; (S.G.); (M.J.A.); (D.P.A.); (S.D.S.); (M.O.B.); (A.S.); (D.H.)
- Correspondence:
| | - Daniel V. Araujo
- Hospital de Base, Faculdade de Medicina de Sao Jose do Rio Preto, Sao Jose do Rio Preto 15090-000, Brazil;
| | - Kerry J. Savage
- Division of Medical Oncology, Department of Medicine, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada;
| | - Tina Cheng
- Department of Oncology, University of Calgary, Calgary, AB T2N 4N2, Canada; (T.C.); (J.G.M.)
| | - Moumita Saha
- Division of Endocrinology and Metabolism, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada; (M.S.); (S.G.)
| | - Xinni Song
- The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON K1H 8L6, Canada;
| | - Sabrina Gill
- Division of Endocrinology and Metabolism, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada; (M.S.); (S.G.)
| | - Jose G. Monzon
- Department of Oncology, University of Calgary, Calgary, AB T2N 4N2, Canada; (T.C.); (J.G.M.)
| | - Debjani Grenier
- Department of Medical Oncology, University of Manitoba, Winnipeg, MB R3A 1R9, Canada;
| | - Sofia Genta
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, University Health Network, Toronto, ON M5S 1Z5, Canada; (S.G.); (M.J.A.); (D.P.A.); (S.D.S.); (M.O.B.); (A.S.); (D.H.)
| | - Michael J. Allen
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, University Health Network, Toronto, ON M5S 1Z5, Canada; (S.G.); (M.J.A.); (D.P.A.); (S.D.S.); (M.O.B.); (A.S.); (D.H.)
| | - Diana P. Arteaga
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, University Health Network, Toronto, ON M5S 1Z5, Canada; (S.G.); (M.J.A.); (D.P.A.); (S.D.S.); (M.O.B.); (A.S.); (D.H.)
| | - Samuel D. Saibil
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, University Health Network, Toronto, ON M5S 1Z5, Canada; (S.G.); (M.J.A.); (D.P.A.); (S.D.S.); (M.O.B.); (A.S.); (D.H.)
| | - Marcus O. Butler
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, University Health Network, Toronto, ON M5S 1Z5, Canada; (S.G.); (M.J.A.); (D.P.A.); (S.D.S.); (M.O.B.); (A.S.); (D.H.)
| | - Anna Spreafico
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, University Health Network, Toronto, ON M5S 1Z5, Canada; (S.G.); (M.J.A.); (D.P.A.); (S.D.S.); (M.O.B.); (A.S.); (D.H.)
| | - David Hogg
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, University Health Network, Toronto, ON M5S 1Z5, Canada; (S.G.); (M.J.A.); (D.P.A.); (S.D.S.); (M.O.B.); (A.S.); (D.H.)
| |
Collapse
|
|
11
|
Kotwal A, Cheung YMM, Cromwell G, Drincic A, Leblebjian H, Quandt Z, Rushakoff RJ, McDonnell ME. Patient-Centered Diabetes Care of Cancer Patients. Curr Diab Rep 2021; 21:62. [PMID: 34902069 DOI: 10.1007/s11892-021-01435-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/02/2021] [Indexed: 12/19/2022]
Abstract
PURPOSE OF REVIEW There is a bidirectional relationship between cancer and diabetes, with one condition influencing the prognosis of the other. Multiple cancer therapies cause diabetes including well-established medications such as glucocorticoids and novel cancer therapies such as immune checkpoint inhibitors (CPIs) and phosphoinositide 3-kinase (PI3K) inhibitors. RECENT FINDINGS The nature and severity of diabetes caused by each therapy differ, with some predominantly mediated by insulin resistance, such as PI3K inhibitors and glucocorticoids, while others by insulin deficiency, such as CPIs. Studies have demonstrated diabetes from CPIs to be more rapidly progressing than conventional type 1 diabetes. There remains a scarcity of published guidance for the screening, diagnosis, and management of hyperglycemia and diabetes from these therapies. The need for such guidance is critical because diabetes management in the cancer patient is complex, individualized, and requires inter-disciplinary care. In the present narrative review, we synthesize and summarize the most relevant literature pertaining to diabetes and hyperglycemia in the setting of these cancer therapies and provide an updated patient-centered framework for their evaluation and management.
Collapse
Affiliation(s)
- Anupam Kotwal
- Division of Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yee-Ming M Cheung
- Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA, 02115, USA
| | - Grace Cromwell
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA, 02115, USA
| | - Andjela Drincic
- Division of Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA
| | - Houry Leblebjian
- Department of Pharmacy, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Zoe Quandt
- Division of Endocrinology and Metabolism, University of California, San Francisco, CA, USA
| | - Robert J Rushakoff
- Division of Endocrinology and Metabolism, University of California, San Francisco, CA, USA
| | - Marie E McDonnell
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA, 02115, USA.
| |
Collapse
|
|
12
|
Yim C, Mansell K, Hussein N, Arnason T. Current cancer therapies and their influence on glucose control. World J Diabetes 2021; 12:1010-1025. [PMID: 34326951 PMCID: PMC8311484 DOI: 10.4239/wjd.v12.i7.1010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/11/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.
Collapse
Affiliation(s)
- Carly Yim
- Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Kerry Mansell
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
| | - Nassrein Hussein
- Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Terra Arnason
- Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| |
Collapse
|
|
13
|
Abstract
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target two key signalling pathways related to T cell activation and exhaustion, by binding to and inhibiting cytotoxic T lymphocyte antigen 4 (CTLA4) or PD1 and its ligand PDL1. ICIs, such as nivolumab, pembrolizumab and ipilimumab, are approved for the treatment of numerous and diverse cancer types, in various combination regimens, and are now an established cornerstone of cancer therapeutics. Toxicities induced by ICIs are autoimmune in nature and are referred to as immune-related adverse events (irAEs); these events can affect any organ system in an unpredictable fashion. Importantly, irAEs can manifest as endocrinopathies involving the thyroid (hypothyroidism or thyrotoxicosis), pituitary (hypophysitis), adrenal glands (adrenal insufficiency) and pancreas (diabetes mellitus). These events are a frequent source of acute and persistent morbidity in patients treated with ICIs and can even be fatal. Over the past few years, there has been a growing understanding of the underlying pathogenesis of irAEs that has led to the development of more effective management strategies. Herein, we review the current understanding of the pathobiology, clinical manifestations and treatment approaches to endocrine toxicities arising from ICIs.
Collapse
Affiliation(s)
- Jordan J Wright
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, USA
| | - Alvin C Powers
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
- VA Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Douglas B Johnson
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, USA.
| |
Collapse
|
|
14
|
Lo Preiato V, Salvagni S, Ricci C, Ardizzoni A, Pagotto U, Pelusi C. Diabetes mellitus induced by immune checkpoint inhibitors: type 1 diabetes variant or new clinical entity? Review of the literature. Rev Endocr Metab Disord 2021; 22:337-349. [PMID: 33409866 DOI: 10.1007/s11154-020-09618-w] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/24/2020] [Indexed: 12/16/2022]
Abstract
Immune Check-Point Inhibitors (CPIs) have improved long-term patients' outcomes in several advanced cancers. Diabetes mellitus induced by CPIs (CPI-DM) is considered the second most frequent endocrine CPIs' side effects with a variable prevalence up to 2%. The aim of our study was to identify CPI-DM characteristics and differences from the classical form of diabetes. Therefore, we conducted a structured Pubmed® search collecting publications dated from January 2015 to December 2019. A total of 642 citations were identified and 121 publications met our study criteria. We analyzed 200 case reports, including our 3 cases under publication. The majority of CPI-DM occurred with anti-Programmed cell Death-1 in monotherapy or in combination, although few cases with Programmed cell Death Ligand-1 and Cytotoxic T Lymphocyte Antigen 4 were reported. Generally, CPI-DM arose early (an average of 9 weeks after CPIs starting), but also after the end of CPIs treatment. In all patients, CPI-DM has an acute onset and in 67.5% of cases diabetic ketoacidosis occurs. C-peptide levels were usually and permanently compromised, requiring lifelong insulin therapy. Moreover, autoimmunity and genetic profile was not always helpful. In particular, anti-glutamic acid decarboxylase (anti-GAD) antibodies and Human Leukocyte Antigen (HLA) DR4 were present in only 43.0% and 51.3% of cases respectively. In 51.0% of subjects a mild exocrine impairment coexisted. In short, though CPI-DM has similarities to type 1 diabetes mellitus, it represents a new, largely unknown, clinical entity. In addition, as CPI-DM is a relative frequent side-effect under CPI, a close monitoring of the glucose levels and early signs and symptoms of diabetes in patients affected by neoplasm is recommended.
Collapse
Affiliation(s)
- V Lo Preiato
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - S Salvagni
- Division of Medical Oncology, Department of Experimental Diagnostic and Speciality Medicine (DIMES), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Bologna, Italy
| | - C Ricci
- Surgical Department, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, Sant'Orsola Hospital, Bologna, Italy
| | - A Ardizzoni
- Division of Medical Oncology, Department of Experimental Diagnostic and Speciality Medicine (DIMES), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Bologna, Italy
| | - U Pagotto
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy.
| | - C Pelusi
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy
| |
Collapse
|
|
15
|
Kang JH, Bluestone JA, Young A. Predicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines. Trends Immunol 2021; 42:293-311. [PMID: 33714688 DOI: 10.1016/j.it.2021.02.006] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/08/2021] [Accepted: 02/08/2021] [Indexed: 12/17/2022]
Abstract
Cancer immunotherapies can successfully activate immune responses towards certain tumors. However, this can also result in the development of treatment-induced immune-related adverse events (irAEs) in multiple tissues. Growing evidence suggests that cytokine production in response to these therapeutics potentiates the development of irAEs and may have predictive value as biomarkers for irAE occurrence. In addition, therapeutic agents that inhibit cytokine activity can limit the severity of irAEs, and their use is being tested in the clinical setting. This review provides an in-depth analysis of strategies to uncouple the cytokine response, that precipitates irAEs following cancer immunotherapies, from the benefit gained in promoting antitumor immunity.
Collapse
Affiliation(s)
- Jee Hye Kang
- Sean N. Parker Autoimmune Research Laboratory and Diabetes Center, University of California San Francisco, San Francisco, CA, USA
| | - Jeffrey A Bluestone
- Sean N. Parker Autoimmune Research Laboratory and Diabetes Center, University of California San Francisco, San Francisco, CA, USA; Sonoma Biotherapeutics, South San Francisco, CA, USA
| | - Arabella Young
- Sean N. Parker Autoimmune Research Laboratory and Diabetes Center, University of California San Francisco, San Francisco, CA, USA; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
| |
Collapse
|
|
16
|
Perdigoto AL, Kluger H, Herold KC. Adverse events induced by immune checkpoint inhibitors. Curr Opin Immunol 2021; 69:29-38. [PMID: 33640598 DOI: 10.1016/j.coi.2021.02.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 01/17/2021] [Accepted: 02/01/2021] [Indexed: 12/17/2022]
Abstract
Immune checkpoint inhibitors have revolutionized the treatments of cancers but are also associated with immune related adverse events that can interfere with their use. The types and severity of adverse events vary with checkpoint inhibitors. A single mechanism of pathogenesis has not emerged: postulated mechanisms involve direct effects of the checkpoint inhibitor, emergence of autoantibodies or autoreactive T cells, and destruction by toxic effects of activated T cells. Several host factors such as genotypes, preexisting autoimmune disease, inflammatory responses and others may have predictive value. Ongoing investigations seek to identify ways of modulating the autoimmunity without affecting the anti-tumor response with agents that are specific for the autoimmune mechanisms.
Collapse
Affiliation(s)
- Ana Luisa Perdigoto
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT, United States
| | - Harriet Kluger
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT, United States
| | - Kevan C Herold
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT, United States.
| |
Collapse
|
|
17
|
Zheng Z, Liu Y, Yang J, Tan C, Zhou L, Wang X, Xiao L, Zhang S, Chen Y, Liu X. Diabetes mellitus induced by immune checkpoint inhibitors. Diabetes Metab Res Rev 2021; 37:e3366. [PMID: 32543027 DOI: 10.1002/dmrr.3366] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/22/2020] [Accepted: 06/12/2020] [Indexed: 02/05/2023]
Abstract
Immune checkpoint inhibitors (ICIs) are widely used in oncology for their favourable antitumor efficacy. ICI therapy is associated with a unique toxicity profile known as immune-related adverse events (irAEs). One such irAE is ICI-related diabetes mellitus (DM), which is relatively uncommon but can become extremely severe, leading to irreversible impairment of β-cells, and even lead to death if not promptly recognised and properly managed. The precise mechanisms of ICI-related DM are not well understood. In this review, we summarise the clinical characteristics, pathophysiology, and management of this adverse effect caused by ICI therapy. Deeper investigation of ICI-related DM may contribute to elucidate the molecular mechanisms of classical type 1 DM.
Collapse
Affiliation(s)
- Zhenjiang Zheng
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ya Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Yang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Chunlu Tan
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Li Zhou
- Research Core Facility of West China Hospital, Sichuan University, Chengdu, China
| | - Xing Wang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Li Xiao
- Department of Traditional Chinese Medicine, Chengdu Third People's Hospital, Chengdu, China
| | - Shu Zhang
- Department of General Surgery, Chengdu Third People's Hospital, Chengdu, China
| | - Yonghua Chen
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xubao Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
18
|
Wu L, Tsang VHM, Sasson SC, Menzies AM, Carlino MS, Brown DA, Clifton-Bligh R, Gunton JE. Unravelling Checkpoint Inhibitor Associated Autoimmune Diabetes: From Bench to Bedside. Front Endocrinol (Lausanne) 2021; 12:764138. [PMID: 34803927 PMCID: PMC8603930 DOI: 10.3389/fendo.2021.764138] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 09/30/2021] [Indexed: 12/14/2022] Open
Abstract
Immune checkpoint inhibitors have transformed the landscape of oncological therapy, but at the price of a new array of immune related adverse events. Among these is β-cell failure, leading to checkpoint inhibitor-related autoimmune diabetes (CIADM) which entails substantial long-term morbidity. As our understanding of this novel disease grows, parallels and differences between CIADM and classic type 1 diabetes (T1D) may provide insights into the development of diabetes and identify novel potential therapeutic strategies. In this review, we outline the knowledge across the disciplines of endocrinology, oncology and immunology regarding the pathogenesis of CIADM and identify possible management strategies.
Collapse
Affiliation(s)
- Linda Wu
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
- Department of Endocrinology, Westmead Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- *Correspondence: Linda Wu,
| | - Venessa H. M. Tsang
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Sarah C. Sasson
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Immunology, Westmead Hospital, Sydney, NSW, Australia
- NSW Health Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Sydney, NSW, Australia
| | - Alexander M. Menzies
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Matteo S. Carlino
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Department of Medical Oncology, Westmead Hospital, Sydney, NSW, Australia
| | - David A. Brown
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Immunology, Westmead Hospital, Sydney, NSW, Australia
- NSW Health Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Sydney, NSW, Australia
| | - Roderick Clifton-Bligh
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Jenny E. Gunton
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Department of Endocrinology, Westmead Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| |
Collapse
|
|
19
|
Scheithauer TPM, Rampanelli E, Nieuwdorp M, Vallance BA, Verchere CB, van Raalte DH, Herrema H. Gut Microbiota as a Trigger for Metabolic Inflammation in Obesity and Type 2 Diabetes. Front Immunol 2020; 11:571731. [PMID: 33178196 PMCID: PMC7596417 DOI: 10.3389/fimmu.2020.571731] [Citation(s) in RCA: 364] [Impact Index Per Article: 72.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/11/2020] [Indexed: 12/12/2022] Open
Abstract
The gut microbiota has been linked to the development of obesity and type 2 diabetes (T2D). The underlying mechanisms as to how intestinal microbiota may contribute to T2D are only partly understood. It becomes progressively clear that T2D is characterized by a chronic state of low-grade inflammation, which has been linked to the development of insulin resistance. Here, we review the current evidence that intestinal microbiota, and the metabolites they produce, could drive the development of insulin resistance in obesity and T2D, possibly by initiating an inflammatory response. First, we will summarize major findings about immunological and gut microbial changes in these metabolic diseases. Next, we will give a detailed view on how gut microbial changes have been implicated in low-grade inflammation. Lastly, we will critically discuss clinical studies that focus on the interaction between gut microbiota and the immune system in metabolic disease. Overall, there is strong evidence that the tripartite interaction between gut microbiota, host immune system and metabolism is a critical partaker in the pathophysiology of obesity and T2D.
Collapse
Affiliation(s)
- Torsten P M Scheithauer
- Department of Internal Medicine, Amsterdam University Medical Center (UMC), Vrije Universiteit (VU) University Medical Center, Amsterdam, Netherlands.,Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, Netherlands
| | - Elena Rampanelli
- Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, Netherlands
| | - Max Nieuwdorp
- Department of Internal Medicine, Amsterdam University Medical Center (UMC), Vrije Universiteit (VU) University Medical Center, Amsterdam, Netherlands.,Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, Netherlands
| | - Bruce A Vallance
- Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, BC, Canada
| | - C Bruce Verchere
- Department of Surgery, University of British Columbia and BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Daniël H van Raalte
- Department of Internal Medicine, Amsterdam University Medical Center (UMC), Vrije Universiteit (VU) University Medical Center, Amsterdam, Netherlands.,Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, Netherlands
| | - Hilde Herrema
- Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, Netherlands
| |
Collapse
|
|
20
|
Quandt Z, Young A, Perdigoto AL, Herold KC, Anderson MS. Autoimmune Endocrinopathies: An Emerging Complication of Immune Checkpoint Inhibitors. Annu Rev Med 2020; 72:313-330. [PMID: 32886542 DOI: 10.1146/annurev-med-050219-034237] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Immune checkpoint inhibitors (CPIs) reverse immune suppression that is thought to allow malignant growth. Despite remarkable efficacy in a subset of cancers, their use is accompanied by immune-related adverse events, including endocrinopathies such as hypophysitis, thyroid dysfunction, diabetes, and adrenalitis. These conditions are heterogenous, with differing incidence across CPI types, but are unified by the acuity and extremity of tissue-specific organ failure. Their occurrence may be associated with beneficial tumor control. Further understanding of the risk factors and mechanisms of these endocrine immunotoxicities can help optimize CPI use as well as improve understanding of spontaneous autoimmune diseases.
Collapse
Affiliation(s)
- Zoe Quandt
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, California 94143, USA; , , .,Diabetes Center, University of California, San Francisco, California 94143, USA
| | - Arabella Young
- Diabetes Center, University of California, San Francisco, California 94143, USA.,QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
| | - Ana Luisa Perdigoto
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
| | - Kevan C Herold
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA; .,Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
| | - Mark S Anderson
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, California 94143, USA; , , .,Diabetes Center, University of California, San Francisco, California 94143, USA
| |
Collapse
|
|
21
|
Mirzaei M, Harismah K, Soleimani M, Mousavi S. Inhibitory effects of curcumin on aldose reductase and cyclooxygenase-2 enzymes. J Biomol Struct Dyn 2020; 39:6424-6430. [DOI: 10.1080/07391102.2020.1800513] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Mahmoud Mirzaei
- Biosensor Research Center, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Kun Harismah
- Department of Chemical Engineering, Faculty of Engineering, Universitas Muhammadiyah Surakarta, Surakarta, Indonesia
| | - Mehdi Soleimani
- Isfahan Pharmacy Students' Research Committee, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sarah Mousavi
- Department of Clinical Pharmacy and Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| |
Collapse
|
|
22
|
Rus Bakarurraini NAA, Ab Mutalib NS, Jamal R, Abu N. The Landscape of Tumor-Specific Antigens in Colorectal Cancer. Vaccines (Basel) 2020; 8:E371. [PMID: 32664247 PMCID: PMC7565947 DOI: 10.3390/vaccines8030371] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 06/22/2020] [Accepted: 06/22/2020] [Indexed: 12/24/2022] Open
Abstract
Over the last few decades, major efforts in cancer research and treatment have intensified. Apart from standard chemotherapy approaches, immunotherapy has gained substantial traction. Personalized immunotherapy has become an important tool for cancer therapy with the discovery of immune checkpoint inhibitors. Traditionally, tumor-associated antigens are used in immunotherapy-based treatments. Nevertheless, these antigens lack specificity and may have increased toxicity. With the advent of next-generation technologies, the identification of new tumor-specific antigens is becoming more important. In colorectal cancer, several tumor-specific antigens were identified and functionally validated. Multiple clinical trials from vaccine-based and adoptive cell therapy utilizing tumor-specific antigens have commenced. Herein, we will summarize the current landscape of tumor-specific antigens particularly in colorectal cancer.
Collapse
Affiliation(s)
| | | | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (N.A.A.R.B.); (N.S.A.M.)
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (N.A.A.R.B.); (N.S.A.M.)
| |
Collapse
|
|
23
|
Li X, Zhong T, Tang R, Wu C, Xie Y, Liu F, Zhou Z. PD-1 and PD-L1 Expression in Peripheral CD4/CD8+ T Cells Is Restored in the Partial Remission Phase in Type 1 Diabetes. J Clin Endocrinol Metab 2020; 105:5814248. [PMID: 32236416 DOI: 10.1210/clinem/dgaa130] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 03/20/2020] [Indexed: 02/06/2023]
Abstract
CONTEXT Partial remission (PR) in type 1 diabetes (T1D) is accompanied by downregulation of the immune response. Programmed cell death-1 (PD-1) and its ligand (PD-L1) are important immunosuppressive molecules, but their changes in the PR phase are unclear. OBJECTIVE We investigated the dynamic changes of PD-1/PD-L1 expression on T cells around the PR phase in T1D. METHODS Ninety-eight T1D patients were recruited cross-sectionally and grouped according to PR status into nonremitters (individuals who did not undergo PR during the disease course; n = 39), pre-PR (n = 15), mid-PR (n = 30), and post-PR (n = 14) subgroups. PR was defined according to C-peptide level ≥300 pmol/L or index of insulin-adjusted hemoglobin A1c ≤9 as recommended. Among all the 98 patients, 29 newly diagnosed individuals were prospectively followed up for 1 year. The dynamic changes of PD-1/PD-L1 expression, frequency of regulatory T cells (Tregs) and IL-35+ Tregs among peripheral CD4/CD8+ T cells were determined. RESULTS PD-1/PD-L1 on CD4+/CD8+ T cells showed a dynamic change around the PR phase: lowest in pre-PR phase, restored in mid-PR phase, and declined again in post-PR phase. Conversely, this pattern did not occur for nonremitters. Notably, PD-1 expression on CD8+ T cells in mid-PR was positively correlated with the length of the PR phase. The percentages of circulating Tregs and IL-35+ Tregs showed no relation to PR. CONCLUSIONS The PR phase is associated with restoration of PD-1/PD-L1 on CD4+ and CD8+ T cells, suggesting that PD-1/PD-L1 may be a potential target for prolonging this phase in T1D.
Collapse
Affiliation(s)
- Xia Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Ting Zhong
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Rong Tang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Chao Wu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Yuting Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Fang Liu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| |
Collapse
|
|
24
|
Quandt Z, Young A, Anderson M. Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes. Clin Exp Immunol 2020; 200:131-140. [PMID: 32027018 PMCID: PMC7160652 DOI: 10.1111/cei.13424] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2020] [Indexed: 12/17/2022] Open
Abstract
Autoimmune diabetes mellitus is a rare but significant side effect of treatment with immune checkpoint inhibitors. Immune checkpoint inhibitor-induced diabetes mellitus (CPI-DM) is characterized by acute onset of dramatic hyperglycemia with severe insulin deficiency and occurrence following exposure to programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors rather than cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors. As a growing number of patients undergo immunotherapy, further understanding of the characteristics of CPI-DM patients is needed for improved prognostic and diagnostic application in order to reduce overall morbidity for this already at-risk population. Additionally, understanding of the features and mechanisms of CPI-DM may contribute to understanding mechanisms of spontaneous type I diabetes mellitus (T1DM). Here, we summarize the clinical features of CPI-DM and interrogate the genetic and cellular mechanisms that may contribute to the disease, as well as the clinical challenges for predicting and treating these patients as increasing cancer immunotherapies reach clinical utility.
Collapse
Affiliation(s)
- Z. Quandt
- Division of Diabetes, Endocrinology and Metabolism, Department of MedicineUniversity of California San FranciscoSan FranciscoCAUSA
- Diabetes CenterUniversity of California San FranciscoSan FranciscoCAUSA
| | - A. Young
- Division of Diabetes, Endocrinology and Metabolism, Department of MedicineUniversity of California San FranciscoSan FranciscoCAUSA
| | - M. Anderson
- Division of Diabetes, Endocrinology and Metabolism, Department of MedicineUniversity of California San FranciscoSan FranciscoCAUSA
- Diabetes CenterUniversity of California San FranciscoSan FranciscoCAUSA
| |
Collapse
|
|
25
|
Dougan M, Pietropaolo M. Time to dissect the autoimmune etiology of cancer antibody immunotherapy. J Clin Invest 2020; 130:51-61. [PMID: 31895048 PMCID: PMC6934191 DOI: 10.1172/jci131194] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory "checkpoint" receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.
Collapse
Affiliation(s)
- Michael Dougan
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Massimo Pietropaolo
- Diabetes Research Center, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| |
Collapse
|
|
26
|
Trinh B, Donath MY, Läubli H. Response to Comment on Trinh et al. Successful Treatment of Immune Checkpoint Inhibitor-Induced Diabetes With Infliximab. Diabetes Care 2019;42:e153-e154. Diabetes Care 2020; 43:e11. [PMID: 31862827 DOI: 10.2337/dci19-0058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Beckey Trinh
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland
| | - Marc Y Donath
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - Heinz Läubli
- Department of Biomedicine, University Hospital Basel, Basel, Switzerland.,Division of Medical Oncology, University Hospital Basel, Basel, Switzerland
| |
Collapse
|
|
27
|
Galligan A, Krishnamurthy B, Kay TW. Comment on Trinh et al. Successful Treatment of Immune Checkpoint Inhibitor-Induced Diabetes With Infliximab. Diabetes Care 2019;42:e153-e154. Diabetes Care 2020; 43:e10. [PMID: 31862826 DOI: 10.2337/dc19-1747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Anna Galligan
- St Vincent's Institute of Medical Research, Fitzroy, Australia .,Department of Medicine, The University of Melbourne, St Vincent's Hospital, Fitzroy, Australia
| | - Balasubramanian Krishnamurthy
- St Vincent's Institute of Medical Research, Fitzroy, Australia.,Department of Medicine, The University of Melbourne, St Vincent's Hospital, Fitzroy, Australia
| | - Thomas W Kay
- St Vincent's Institute of Medical Research, Fitzroy, Australia.,Department of Medicine, The University of Melbourne, St Vincent's Hospital, Fitzroy, Australia
| |
Collapse
|