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      Immunotherapy-Associated Pancreatic Adverse Events: Current Understanding of Their Mechanism, Diagnosis, and Management

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          Abstract

          Immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 (PD-1) and its ligand PD-L1 and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies, are involved in T cell-mediated immune response augmentation and promote anti-tumor immunity. Cancer patients treated with combination of immunotherapy, chemotherapy, radiotherapy, and targeted therapy exhibit superior clinical outcomes and tolerance compared with patients treated with monotherapies. However, immutherapy is associated with several concomitant immune-related adverse events (irAEs). For instance, IrAEs interferes with function of gastrointestinal tract, endocrine, dermatological, nervous system and musculoskeletal systems. ICIs-associated pancreatic injury might causes decrease in endocrine and exocrine pancreatic function, resulting in metabolic and nutritional disorders. Clinicians who administer immune checkpoint inhibitors to cancer patients are diagnosed with hyperglycemia, abdominal pain and steatorrhea. Currently, the precise mechanism of ICIs-associated pancreatic injury has not been fully explored. This paper summarizes incidence, diagnosis, clinical characteristics, potential mechanisms, and treatment management patterns of ICIs-associated pancreatic AEs based on previous studies. In addition, possible management approaches of these adverse effects are presented in this paper. in the findings summarized in this paper lay a basis for management of ICIs-associated pancreatic AEs and expanding future immunotherapy applications.

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          Most cited references74

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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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            Type 2 diabetes as an inflammatory disease.

            Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease.
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              Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors

              Insulin-dependent diabetes may occur in patients with cancers who are treated with checkpoint inhibitors (CPIs). We reviewed cases occurring over a 6-year period at two academic institutions and identified 27 patients in whom this developed, or an incidence of 0.9%. The patients had a variety of solid-organ cancers, but all had received either anti–PD-1 or anti–PD-L1 antibodies. Diabetes presented with ketoacidosis in 59%, and 42% had evidence of pancreatitis in the peridiagnosis period. Forty percent had at least one positive autoantibody and 21% had two or more. There was a predominance of HLA-DR4, which was present in 76% of patients. Other immune adverse events were seen in 70%, and endocrine adverse events in 44%. We conclude that autoimmune, insulin-dependent diabetes occurs in close to 1% of patients treated with anti–PD-1 or –PD-L1 CPIs. This syndrome has similarities and differences compared with classic type 1 diabetes. The dominance of HLA-DR4 suggests an opportunity to identify those at highest risk of these complications and to discover insights into the mechanisms of this adverse event.

                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                25 February 2021
                2021
                : 11
                : 627612
                Affiliations
                [1] 1 Department of Pancreatic Surgery, West China Hospital, Sichuan University , Chengdu, China
                [2] 2 Core Facilities, West China Hospital, Sichuan University , Chengdu, China
                [3] 3 CAAC Academy, Civil Aviation Flight University of China , Guanghan, China
                [4] 4 Lung Cancer Center, West China Hospital, Sichuan University , Chengdu, China
                Author notes

                Edited by: Franz Rödel, University Hospital Frankfurt, Germany

                Reviewed by: Emily Jane Gallagher, Icahn School of Medicine at Mount Sinai, United States; Shaheen Khan, University of Texas Southwestern Medical Center, United States

                *Correspondence: Xubao Liu, xbliu@ 123456medmail.com.cn ; Kezhou Li, huaxipancreas@ 123456163.com

                †These authors have contributed equally to this work

                This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2021.627612
                7959713
                33732647
                d9cee070-b0e4-4ed9-8cf4-9d00f34b9714
                Copyright © 2021 Liu, Zhang, Zhou, Li, Yang, Li, Li and Liu

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 November 2020
                : 18 January 2021
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 74, Pages: 11, Words: 6602
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                immune checkpoint inhibitors,immune-related adverse events,icis associated with diabetes mellitus,amylase/lipase,pancreatitis,pancreatic exocrine insufficiency

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