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      Redirecting T Cells against Epstein–Barr Virus Infection and Associated Oncogenesis

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          Abstract

          The Epstein–Barr virus (EBV) is associated with lymphomas and carcinomas. For some of these, the adoptive transfer of EBV specific T cells has been therapeutically explored, with clinical success. In order to avoid naturally occurring EBV specific autologous T cell selection from every patient, the transgenic expression of latent and early lytic viral antigen specific T cell receptors (TCRs) to redirect T cells, to target the respective tumors, is being developed. Recent evidence suggests that not only TCRs against transforming latent EBV antigens, but also against early lytic viral gene products, might be protective for the control of EBV infection and associated oncogenesis. At the same time, these approaches might be more selective and cause less collateral damage than targeting general B cell markers with chimeric antigen receptors (CARs). Thus, EBV specific TCR transgenic T cells constitute a promising therapeutic strategy against EBV associated malignancies.

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          Most cited references69

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          Epstein-Barr virus: exploiting the immune system.

          In vitro, Epstein-Barr virus (EBV) will infect any resting B cell, driving it out of the resting state to become an activated proliferating lymphoblast. Paradoxically, EBV persists in vivo in a quiescent state in resting memory B cells that circulate in the peripheral blood. How does the virus get there, and with such specificity for the memory compartment? An explanation comes from the idea that two genes encoded by the virus--LMP1 and LMP2A--allow EBV to exploit the normal pathways of B-cell differentiation so that the EBV-infected B blast can become a resting memory cell.
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            EBV persistence in memory B cells in vivo.

            Epstein-Barr virus establishes latency in vitro by activating human B cells to become proliferating blasts, but in vivo it is benign. In the peripheral blood, the virus resides latently in resting B cells that we now show are restricted to the sIgD memory subset. However, in tonsils the virus shows no such restriction. We propose that EBV indiscriminately infects B cells in mucosal lymphoid tissue and that these cells differentiate to become resting memory B cells that then enter the circulation. Activation to the blastoid stage of latency is an essential intermediate step in this process. Thus, EBV may persist by exploiting the mechanisms that produce and maintain long-term B cell memory.
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              Emerging Cellular Therapies for Cancer

              Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that engineered immune cells can serve as a powerful new class of cancer therapeutics. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function. Advances in T cell engineering, genetic editing, the selection of optimal lymphocytes, and cell manufacturing have the potential to broaden T cell–based therapies and foster new applications beyond oncology, in infectious diseases, organ transplantation, and autoimmunity.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                04 June 2020
                June 2020
                : 9
                : 6
                : 1400
                Affiliations
                Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, 8057 Zürich, Switzerland; christian.muenz@ 123456uzh.ch
                Author information
                https://orcid.org/0000-0001-6419-1940
                Article
                cells-09-01400
                10.3390/cells9061400
                7349826
                32512847
                288ecefa-9e58-45e2-a6d0-2d98fc04ccf7
                © 2020 by the author.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 April 2020
                : 03 June 2020
                Categories
                Review

                t cell receptor,chimeric antigen receptor,adoptive t cell transfer,diffuse large b cell lymphoma,nasopharyngeal carcinoma,latent membrane protein,ebv nuclear antigen

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