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      Cytotoxic T Lymphocyte Therapy for Epstein-Barr Virus + Hodgkin's Disease

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          Abstract

          Epstein Barr virus (EBV) + Hodgkin's disease (HD) expresses clearly identified tumor antigens derived from the virus and could, in principle, be a target for adoptive immunotherapy with viral antigen–specific T cells. However, like most tumor-associated antigens in immunocompetent hosts, these potential targets are only weakly immunogenic, consisting primarily of the latent membrane protein (LMP)1 and LMP2 antigens. Moreover, Hodgkin tumors possess a range of tumor evasion strategies. Therefore, the likely value of immunotherapy with EBV-specific cytotoxic effector cells has been questioned. We have now used a combination of gene marking, tetramer, and functional analyses to track the fate and assess the activity of EBV cytotoxic T lymphocyte (CTL) lines administered to 14 patients treated for relapsed EBV + HD. Gene marking studies showed that infused effector cells could further expand by several logs in vivo, contribute to the memory pool (persisting up to 12 mo), and traffic to tumor sites. Tetramer and functional analyses showed that T cells reactive with the tumor-associated antigen LMP2 were present in the infused lines, expanded in peripheral blood after infusion, and also entered tumor. Viral load decreased, demonstrating the biologic activity of the infused CTLs. Clinically, EBV CTLs were well tolerated, could control type B symptoms (fever, night sweats, and weight loss), and had antitumor activity. After CTL infusion, five patients were in complete remission at up to 40 mo, two of whom had clearly measurable tumor at the time of treatment. One additional patient had a partial response, and five had stable disease. The performance and fate of these human tumor antigen–specific T cells in vivo suggests that they might be of value for the treatment of EBV + Hodgkin lymphoma.

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          Most cited references42

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          Report of the Committee on Hodgkin's Disease Staging Classification.

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            The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell.

            Epstein-Barr virus-infected B cells in vivo demonstrate three distinct patterns of latent gene expression, depending on the differentiation stage of the cell. Tonsillar naive B cells express the EBNA2-dependent lymphoblastoid phenotype, characteristic of direct infection. Germinal center centroblasts and centrocytes as well as tonsillar memory B cells express a more restricted pattern of latent genes (EBNA1(Q-K)+, LMP1+, LMP2+, EBNA2-) that has only been seen previously in EBV-positive tumors. Peripheral memory cells express an even more restricted pattern where no latent genes are expressed, with the possible exception of LMP2. These results are consistent with a model where EBV uses the normal biology of B lymphocytes to gain access to and persist within the long-lived memory B cell compartment.
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              Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1.

              The Epstein-Barr virus (EBV) encoded nuclear antigen (EBNA) 1 is expressed in latently infected B lymphocytes that persist for life in healthy virus carriers and is the only viral protein regularly detected in all EBV associated malignancies. The Gly-Ala repeat domain of EBNA1 was shown to inhibit in cis the presentation of major histocompatibility complex (MHC) class I restricted cytotoxic T cell epitopes from EBNA4. It appears that the majority of antigens presented via the MHC I pathway are subject to ATP-dependent ubiquitination and degradation by the proteasome. We have investigated the influence of the repeat on this process by comparing the degradation of EBNA1, EBNA4, and Gly-Ala containing EBNA4 chimeras in a cell-free system. EBNA4 was efficiently degraded in an ATP/ubiquitin/proteasome-dependent fashion whereas EBNA1 was resistant to degradation. Processing of EBNA1 was restored by deletion of the Gly-Ala domain whereas insertion of Gly-Ala repeats of various lengths and in different positions prevented the degradation of EBNA4 without appreciable effect on ubiquitination. Inhibition was also achieved by insertion of a Pro-Ala coding sequence. The results suggest that the repeat may affect MHC I restricted responses by inhibiting antigen processing via the ubiquitin/proteasome pathway. The presence of regularly interspersed Ala residues appears to be important for the effect.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                20 December 2004
                : 200
                : 12
                : 1623-1633
                Affiliations
                [1 ]Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030
                [2 ]Department of Pediatrics, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030
                [3 ]Department of Pathology, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030
                [4 ]Department of Medicine, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030
                [5 ]St. Jude Children's Research Hospital, Memphis, TN 38105
                [6 ]Heinrich Heine University, 40225 Dusseldorf, Germany
                Author notes

                Address correspondence to Catherine M. Bollard, Center for Gene and Cell Therapy, Baylor College of Medicine, 6621 Fannin St., MC 3-3320, Houston, TX 77030. Phone: (832) 824-4781; Fax: (832) 825-4668; email: cmbollar@ 123456txccc.org

                Article
                20040890
                10.1084/jem.20040890
                2211993
                15611290
                490cdded-0864-4f2d-89b5-363d7d87ba0a
                Copyright © 2004, The Rockefeller University Press
                History
                : 5 May 2004
                : 9 November 2004
                Categories
                Article

                Medicine
                gene marking,immunotherapy,epstein-barr virus,lymphoma,lmp2
                Medicine
                gene marking, immunotherapy, epstein-barr virus, lymphoma, lmp2

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