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      Cardiovascular toxicities associated with immune checkpoint inhibitors

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          Abstract

          Cardiovascular toxicities associated with immune checkpoint inhibitors (ICIs) have been reported in case series but have been underappreciated due to their recent emergence, difficulties in diagnosis and non-specific clinical manifestations. ICIs are antibodies that block negative regulators of the T cell immune response, including cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and PD-1 ligand (PD-L1). While ICIs have introduced a significant mortality benefit in several cancer types, the augmented immune response has led to a range of immune-related toxicities, including cardiovascular toxicity. ICI-associated myocarditis often presents with arrhythmias, may co-exist with myositis and myasthenia gravis, can be severe, and portends a poor prognosis. In addition, pericardial disease, vasculitis, including temporal arteritis, and non-inflammatory heart failure, have been recently described as immune-related toxicities from ICI. This narrative review describes the epidemiology, diagnosis, pathophysiology, and treatment of cardiovascular toxicities of ICI therapy, highlighting recent developments in the field in the past year.

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          Most cited references45

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          Is Open Access

          Cancer immunotherapy: the beginning of the end of cancer?

          These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies.
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            Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis

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              BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1.

              During activation, T cells express receptors for receiving positive and negative costimulatory signals. Here we identify the B and T lymphocyte attenuator (BTLA), an immunoglobulin domain-containing glycoprotein with two immunoreceptor tyrosine-based inhibitory motifs. BTLA is not expressed by naive T cells, but it is induced during activation and remains expressed on T helper type 1 (T(H)1) but not T(H)2 cells. Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and association with the Src homology domain 2 (SH2)-containing protein tyrosine phosphatases SHP-1 and SHP-2, and attenuates production of interleukin 2 (IL-2). BTLA-deficient T cells show increased proliferation, and BTLA-deficient mice have increased specific antibody responses and enhanced sensitivity to experimental autoimmune encephalomyelitis. B7x, a peripheral homolog of B7, is a ligand of BTLA. Thus, BTLA is a third inhibitory receptor on T lymphocytes with similarities to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1).
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                Author and article information

                Journal
                Cardiovascular Research
                Oxford University Press (OUP)
                0008-6363
                1755-3245
                February 02 2019
                February 02 2019
                Affiliations
                [1 ]Division of Cardiology, Cardio-Oncology Program, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, USA
                [2 ]Division of Cardiology, Johns Hopkins University School of Medicine, 600 N Wolfe St, Baltimore, MD, 21287, USA
                [3 ]Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD, 21287, USA
                [4 ]Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD, 21287, USA
                [5 ]Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, 675 Charles E Young Dr S, Los Angeles, CA, 90095, USA
                [6 ]Department of Translational Medical Sciences, Interdepartmental Center for Clinical and Translational Research (CIRCET), Federico II University, Via Pansini 5, Naples, NA, 80131, Italy
                [7 ]Cardio-Oncology Service, Royal Brompton Hospital, Dovehouse St, London SW3 6LY, UK
                [8 ]National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK
                [9 ]Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA, 02115, USA
                [10 ]Division of Hematology-Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN, 37232, USA
                Article
                10.1093/cvr/cvz026
                6452314
                30715219
                6393e89a-5c0e-4f4a-8ca0-c230b29d68e3
                © 2019

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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