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      Is Open Access

      Common endocrine system adverse events associated with immune checkpoint inhibitors ☆

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          Abstract

          Immune checkpoint inhibitors (ICIs), a novel anti-tumor therapeutic modality, are monoclonal antibodies targeting certain immune checkpoints (ICs) that reactivate T cells to achieve anti-tumor immunity by targeting, binding, and blocking ICs. Targeted inhibitory antibodies against the ICs cytotoxic T-lymphocyte antigen and programmed death receptor-1 have demonstrated efficacy and durable anti-tumor activity in patients with cancer. ICs may prevent autoimmune reactions. However, ICIs may disrupt ICs properties and trigger autoimmune-related adverse reactions involving various organ systems including the cardiovascular, pulmonary, gastrointestinal, renal, musculoskeletal, dermal, and endocrine systems. Approximately 10% of patients with damage to target organs such as the thyroid, pituitary, pancreas, and adrenal glands develop endocrine system immune-related adverse events (irAEs) such as thyroid dysfunction, pituitary gland inflammation, diabetes mellitus, and primary adrenal insufficiency. However, the symptoms of immunotherapy-associated endocrine system irAEs may be nonspecific and similar to those of other treatment-related adverse reactions, and failure to recognize them early may lead to death. Timely detection and treatment of immunotherapy-associated endocrine irAEs is essential to improve the efficacy of immunotherapy, prognosis, and the quality of life of patients. This study aimed to review the mechanisms by which ICIs cause endocrine irAEs providing guidance for the development of appropriate management protocols. Here, we discuss (1) the biological mechanisms of ICs in tumorigenesis and progression, focusing on cytotoxic T-lymphocyte antigen and programmed cell death-1/programmed cell death-ligand 1; and (2) the epidemiology, clinical symptoms, diagnosis, and treatment of four immunotherapy-related endocrine complications.

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          Highlights

          • •

            This review summarizes common endocrine immune-related adverse events (irAEs) after immunotherapy by endocrine organs.

          • •

            The mechanisms underlying irAEs in each endocrine organ were analyzed.

          • •

            Timely detection and treatment of immunotherapy-associated endocrine irAEs is essential to improve immunotherapy efficacy.

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          Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

          F. Stephen Hodi, Steven J O'Day, David F McDermott … (2010)
          An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
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            Cancer immunotherapy using checkpoint blockade

            Jedd Wolchok, Antoni Ribas (2018)
            The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte antigen-4 (CTLA-4) or the programmed death-1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the pre-existence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long lasting disease control, yet one third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon gamma signaling pathways. New generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.
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              PD-1 and its ligands in tolerance and immunity.

              Mary E. Keir, Manish J. Butte, Gordon J. Freeman … (2008)
              Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. The identification of B7-1 as an additional binding partner for PD-L1, together with the discovery of an inhibitory bidirectional interaction between PD-L1 and B7-1, reveals new ways the B7:CD28 family regulates T cell activation and tolerance. In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential.
              Article 0 comments Cited 939 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yintao Li
                Journal
                Journal ID (nlm-ta): Cancer Pathog Ther
                Journal ID (iso-abbrev): Cancer Pathog Ther
                Title: Cancer Pathogenesis and Therapy
                Publisher: Elsevier
                ISSN (Print): 2097-2563
                ISSN (Electronic): 2949-7132
                Publication date PMC-release: 01 December 2023
                Publication date Collection: July 2024
                Publication date (Electronic): 01 December 2023
                Volume: 2
                Issue: 3
                Pages: 164-172
                Affiliations
                [a ]Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
                [b ]Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
                [c ]National Institutes for Food and Drug Control, Beijing 102629, China
                [d ]Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250000, China
                [e ]Department of Medical Oncology, Shandong Cancer Hospital and Institute, Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, Shandong 261000, China
                Author notes
                [∗ ]Corresponding author: Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China. yintaoli@ 123456fudan.edu.cn
                [1]

                Ying Li, Junfeng Zhao and Yue Wang contributed equally to this work.

                Article
                Publisher Item ID: S2949-7132(23)00094-0
                DOI: 10.1016/j.cpt.2023.11.005
                PMC ID: 11252504
                PubMed ID: 39027145
                SO-VID: 749b9c60-0d0e-4cc7-bf5c-351ef945b7cb
                Copyright © © 2023 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 1 August 2023
                Date revision received : 23 November 2023
                Date accepted : 28 November 2023
                Categories
                Subject: Review Article

                Keywords: immune checkpoint inhibitors,immune checkpoints,cytotoxic t-lymphocyte antigen 4,programmed cell death-1,programmed cell death-ligand 1,endocrine autoimmune-related adverse reactions
                Data availability:
                Keywords: immune checkpoint inhibitors, immune checkpoints, cytotoxic t-lymphocyte antigen 4, programmed cell death-1, programmed cell death-ligand 1, endocrine autoimmune-related adverse reactions

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