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      Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline

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          Abstract

          Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but are associated with significant autoimmune endocrinopathies that pose both diagnostic and treatment challenges. The aim of this guideline is to provide clinicians with the best possible evidence-based recommendations for treatment and follow-up of patients with ICI-induced endocrine side-effects based on the Grading of Recommendations Assessment, Development, and Evaluation system. As these drugs have been used for a relatively short time, large systematic investigations are scarce. A systematic approach to diagnosis, treatment, and follow-up is needed, including baseline tests of endocrine function before each treatment cycle. We conclude that there is no clear evidence for the benefit of high-dose glucocorticoids to treat endocrine toxicities with the possible exceptions of severe thyroid eye disease and hypophysitis affecting the visual apparatus. With the exception of thyroiditis, most endocrine dysfunctions appear to be permanent regardless of ICI discontinuation. Thus, the development of endocrinopathies does not dictate a need to stop ICI treatment.

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          Most cited references152

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Cancer immunotherapy using checkpoint blockade

            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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              Fundamental Mechanisms of Immune Checkpoint Blockade Therapy

              Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge.Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069-86. ©2018 AACR.

                Author and article information

                Journal
                Eur J Endocrinol
                Eur J Endocrinol
                EJE
                European Journal of Endocrinology
                Bioscientifica Ltd (Bristol )
                0804-4643
                1479-683X
                23 September 2022
                01 December 2022
                : 187
                : 6
                : G1-G21
                Affiliations
                [1 ]Department of Clinical Science and K.G. Jebsen Center of Autoimmune Diseases , University of Bergen, Bergen, Norway
                [2 ]Department of Medicine , Haukeland University Hospital, Bergen, Norway
                [3 ]Aix Marseille Univ , INSERM U1251, Marseille Medical genetics, Department of Endocrinology, Assistance Publique-Hopitaux de Marseille, 13005 Marseille, France
                [4 ]Department of Endocrinology , University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
                [5 ]Department of Oncology and Hematology , University of Milan, European Institute of Oncology, IRCCS, Milan, Italy
                [6 ]Department of Endocrinology , University Hospitals Leuven, Leuven, Belgium
                [7 ]Pituitary Center , Department of Medicine and Neurological Surgery, Oregon Health & Science University, Portland, Oregon, USA
                [8 ]Department of Endocrinology , Christie Hospital NHS Foundation Trust, University of Manchester, Manchester, UK
                [9 ]Endocrine Unit , Pisa University Hospital, Pisa, Italy
                [10 ]Endocrine Unit and Diabetes Centre , Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
                [11 ]Department of Internal Medicine and Oncology , ENETS Center of Excellence, Faculty of Medicine, Semmelweis University, Budapest, Hungary
                [12 ]Department of Medical Oncology
                [13 ]Department of Clinical Epidemiology , Leiden University Medical Center, Leiden, The Netherlands
                Author notes
                Correspondence should be addressed to E S Husebye; Email: eyhu@ 123456helse-bergen.no
                Author information
                http://orcid.org/0000-0002-7886-2976
                http://orcid.org/0000-0002-1808-8800
                http://orcid.org/0000-0001-9284-6289
                http://orcid.org/0000-0002-0651-1376
                http://orcid.org/0000-0002-1333-7580
                Article
                EJE-22-0689
                10.1530/EJE-22-0689
                9641795
                36149449
                2a454957-d53f-4b19-bf2a-35e95638f714
                © The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 08 August 2022
                : 23 September 2022
                Categories
                Clinical Practice Guideline

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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