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      T-Cell Therapy: Options for Infectious Diseases

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          Abstract

          The emergence of drug-resistant tuberculosis is challenging tuberculosis control worldwide. In the absence of an effective vaccine to prevent primary infection with Mycobacterium tuberculosis and tuberculosis disease, host-directed therapies may offer therapeutic options, particularly for patients with multidrug-resistant and extensively drug-resistant tuberculosis where prognosis is often limited. CD8 + and CD4 + T cells mediate antigen-specific adaptive cellular immune responses. Their use in precision immunotherapy in clinical conditions, especially in treating cancer as well as for prevention of life-threatening viral infections in allogeneic transplant recipients, demonstrated safety and clinical efficacy. We review key achievements in T-cell therapy, including the use of recombinant immune recognition molecules (eg, T-cell receptors and CD19 chimeric antigen receptors), and discuss its potential in the clinical management of patients with drug-resistant and refractory tuberculosis failing conventional therapy.

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          Most cited references76

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          Current concepts in the diagnosis and management of cytokine release syndrome.

          As immune-based therapies for cancer become potent, more effective, and more widely available, optimal management of their unique toxicities becomes increasingly important. Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed following administration of natural and bispecific antibodies and, more recently, following adoptive T-cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including interleukin (IL)-6 and interferon γ, and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL-6 receptor antibody, with or without corticosteroids, can reverse the syndrome. However, because early and aggressive immunosuppression could limit the efficacy of the immunotherapy, current approaches seek to limit administration of immunosuppressive therapy to patients at risk for life-threatening consequences of the syndrome. This report presents a novel system to grade the severity of CRS in individual patients and a treatment algorithm for management of CRS based on severity. The goal of our approach is to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of CRS.
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            Adoptive cell transfer as personalized immunotherapy for human cancer.

            Adoptive cell therapy (ACT) is a highly personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity. ACT using naturally occurring tumor-reactive lymphocytes has mediated durable, complete regressions in patients with melanoma, probably by targeting somatic mutations exclusive to each cancer. These results have expanded the reach of ACT to the treatment of common epithelial cancers. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment. Copyright © 2015, American Association for the Advancement of Science.
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              Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.

              We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.
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                Author and article information

                Journal
                Clin Infect Dis
                Clin. Infect. Dis
                cid
                cid
                Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
                Oxford University Press
                1058-4838
                1537-6591
                15 October 2015
                16 September 2015
                16 September 2015
                : 61
                : Suppl 3 , Advances in Tuberculosis Research: A Blueprint for Opportunities
                : S217-S224
                Affiliations
                [1 ]Therapeutic Immunology Division, Department of Laboratory Medicine, Karolinska Institutet
                [2 ]Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital , Solna, Sweden
                [3 ]Division of Clinical Infectious Diseases, German Center for Infection Research, Research Center Borstel
                [4 ]International Health/Infectious Diseases, University of Lübeck , Germany
                [5 ]Department of Medicine, Karolinska Institutet
                [6 ]Pancreatic Surgery Unit, Division of Surgery, Department of Clinical Science, Intervention and Technology
                [7 ]Department of Neurosurgery, Karolinska University Hospital , Stockholm, Sweden
                [8 ]Department of Infection, Division of Infection and Immunity, Centre for Clinical Microbiology , University College London
                [9 ]National Institute for Health Research Biomedical Research Centre, University College London Hospitals , United Kingdom
                Author notes
                Correspondence: Markus Maeurer, MD, PhD, FRCP (London), Therapeutic Immunology, F79, LabMed, Hälsovägen, Karolinska University Hospital, Huddinge, SE-14186 Huddinge, Sweden ( markus.maeurer@ 123456ki.se ).
                Article
                civ615
                10.1093/cid/civ615
                4583575
                26409284
                f5b54f84-50ad-4ceb-b14a-704493b18ab0
                © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com .

                History
                Funding
                Funded by: UK Medical Research Council
                Funded by: European Union
                Award ID: FW7 Rid-RTI
                Funded by: European Developing Countries Clinical Trials Partnership
                Funded by: UBS Optimus Foundation
                Funded by: National Institute of Health Research Biomedical Research Centre
                Funded by: European Developing Countries Clinical Trials Partnership
                Categories
                Advances in Tuberculosis Research: A Blueprint for Opportunities

                Infectious disease & Microbiology
                t-cells,adoptive cell therapy,mtb,car,host-directed therapy
                Infectious disease & Microbiology
                t-cells, adoptive cell therapy, mtb, car, host-directed therapy

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