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• W2116779494 abstract "ImmunotherapyVol. 6, No. 6 EditorialFree AccessEpstein–Barr virus-specific adoptive immunotherapy: a new horizon for multiple sclerosis treatment?Michael P Pender & Rajiv KhannaMichael P PenderAuthor for correspondence: E-mail Address: m.pender@uq.edu.auThe University of Queensland, School of Medicine, Brisbane, Queensland, AustraliaDepartment of Neurology, Royal Brisbane & Women's Hospital, Brisbane, Queensland, AustraliaQIMR Centre for Immunotherapy & Vaccine Development & Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, AustraliaSearch for more papers by this author & Rajiv KhannaThe University of Queensland, School of Medicine, Brisbane, Queensland, AustraliaQIMR Centre for Immunotherapy & Vaccine Development & Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, AustraliaSearch for more papers by this authorPublished Online:21 Jul 2014https://doi.org/10.2217/imt.14.43AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: adoptive immunotherapyB cellCD8 T cellEpstein–Barr virusmultiple sclerosistreatmentMultiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the CNS causing progressive disability and affecting 2.5 million people worldwide. Usually, the disease has a relapsing–remitting course, with repeated neurologic episodes, each of which is followed by partial or complete recovery and a period free of new symptoms. Most patients with relapsing–remitting MS eventually develop secondary progressive MS, in which there is progressive deterioration independent of relapses. In approximately 10% of patients, MS follows a primary progressive course, with a progressive neurologic deterioration from the onset, sometimes with superimposed relapses. Currently, there is no effective disease-modifying therapy for progressive MS.Over the last 30 years, there has been increasing evidence that Epstein–Barr virus (EBV) has a role in the pathogenesis of MS [1,2]. EBV infection appears to be present in 100% of MS patients when two independent methods are used to determine EBV seropositivity [3]. Prospective studies have shown that primary EBV infection occurs on average 5.6 years before the onset of MS [4] and that high titers of serum IgG antibodies to EBV nuclear antigen-1 (EBNA1) increase the risk of developing MS [5,6]. Infectious mononucleosis also increases the risk of MS [7].In 2003, the novel hypothesis was proposed that human chronic autoimmune diseases, including MS, are caused by EBV infection of autoreactive B cells, which accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells that would otherwise die in the target organ by activation-induced apoptosis [8]. It also postulates that the accumulation of EBV-infected autoreactive B cells in the target organ is due to a genetically determined defect in the elimination of EBV-infected B cells by the cytotoxic CD8+ T cells that normally keep EBV infection under tight control. The hypothesis makes predictions that have subsequently been verified, namely: the presence of EBV-infected B cells in the brain in MS [9,10]; a beneficial effect in MS of rituximab, which kills B cells, including EBV-infected B cells [11]; decreased CD8+ T-cell immunity to EBV in MS [12]; and EBV infection of autoreactive plasma cells in the synovium in rheumatoid arthritis [13]. It also predicts that boosting CD8+ T-cell control of EBV by vaccination or by adoptive immunotherapy will prevent and successfully treat chronic autoimmune diseases.AdE1-LMPpoly is a novel recombinant adenovirus vector encoding multiple CD8+ T-cell epitopes from three EBV latent proteins, namely EBNA1, latent membrane protein (LMP) 1 and LMP2A [14]. Adoptive immunotherapy with autologous T cells expanded in vitro with AdE1-LMPpoly increases survival in patients with metastatic nasopharyngeal carcinoma, a disease in which the carcinoma cells are infected with EBV and express EBNA1, LMP1 and LMP2A [14]. Because EBV-infected B cells in the brain in MS express the same three EBV proteins [9,15], adoptive immunotherapy with AdE1-LMPpoly may be an effective way to increase the number of CD8+ T cells available to eliminate EBV-infected B cells from the CNS in MS. Recently, we reported the first use of adoptive immunotherapy with AdE1-LMPpoly to treat a patient with MS [16].The patient was a 42-year-old man with secondary progressive MS. His first attack of MS occurred in 1994 when he was IgG seropositive for EBNA and EBV viral capsid antigen but IgM seronegative for viral capsid antigen, indicating past infection with EBV. The course of his MS was relapsing–remitting until 2004, when it became secondary progressive. From 2000 to 2008, he was treated with IFN-β-1b. Since 2008, he had been unable to walk or transfer himself. By 2012, intention tremor was progressively limiting the use of his hands and he had a flexion contracture of the right knee. The proportion of EBV-specific CD8+ T cells in his blood was below the tenth percentile in healthy EBV carriers and he carried HLA-A2 and HLA-B7, which are restricting elements for several of the EBNA1, LMP1 and LMP2A epitopes in AdE1-LMPpoly. He also had the general CD8+ T-cell deficiency and an increased CD4:CD8 ratio typical of MS [17].This treatment was approved by the Royal Brisbane and Women's Hospital Clinical Ethical Review Group and through the Special Access Scheme (category B) of the Australian Government Therapeutic Goods Administration. With informed consent, we collected 400 ml of blood and expanded his EBV-specific T cells by in vitro stimulation with AdE1-LMPpoly and IL-2 [14]. After expansion, 38.46% of CD8+ T cells but only 0.22% of CD4+ T cells reacted to the LMP peptides. The EBV-specific T cells were returned to the patient intravenously at fortnightly intervals. To reduce the risk of aggravating CNS inflammation, we chose an initial dose of 5 × 106 T cells, which was only 25% of the median dose used for nasopharyngeal carcinoma [14], and escalated the dose gradually over the following three infusions to 1 × 107, 1.5 × 107 and 2 × 107 cells.The treatment was successfully completed without significant adverse effects. In particular, there were no fevers, influenza-like symptoms or malaise. Following the treatment, he experienced a reduction in fatigue and painful lower limb spasms, an improvement in cognition and hand function, and increased productivity at work. These improvements were sustained up to the time of the latest review, 21 weeks after the final T-cell infusion, when neurological examination demonstrated increased voluntary movement of his lower limbs. Following treatment the frequency of circulating EBV-specific CD8+ T cells increased and there were decreases in intrathecal IgG production and disease activity on magnetic resonance imaging of the brain.These beneficial effects of EBV-specific adoptive immunotherapy in our patient can be explained by the killing of EBV-infected B cells in the CNS by the adoptively transferred CD8+ T cells. The EBV-encoded LMP2A and LMP1 proteins targeted by the transferred CD8+ T cells are crucial in allowing EBV-infected B cells to multiply and mature into memory B cells and plasma cells capable of producing large amounts of antibody. LMP2A and LMP1 mimic the antigen-activated B-cell receptor and the activated CD40 receptor, respectively [18,19]. While the EBV-infected autoreactive B cells in the brain may be driving the autoimmune attack on the brain by producing pathogenic autoantibodies and providing costimulatory survival signals to autoreactive T cells [8], the autoimmune process itself could promote the survival, proliferation and differentiation of the EBV-infected autoreactive B cells by releasing CNS antigens and giving CD4+ T-cell help, which would complement the B-cell receptor and CD40 receptor signaling already provided by LMP2A and LMP1, respectively [20] – that is ‘double signaling’. This could lead to a vicious circle wherein EBV-infected autoreactive B cells promote autoimmunity, which in turn promotes EBV infection in the CNS. Such extensive double signaling through the B-cell receptor and CD40 pathways in the target organ of patients with chronic autoimmune diseases could be a relatively new experience for EBV in its 40 million years of coevolution with primates. Further research is needed to determine whether EBV-infected B cells and plasma cells in the MS brain are autoreactive, as has recently been shown for EBV-infected plasma cells in the synovium of patients with rheumatoid arthritis [13].The adoptive transfer of EBV-specific CD8+ T cells in MS is not without risk. The transferred T cells could aggravate inflammation in the CNS and actually worsen MS, either through cross-reactivity between EBV and CNS antigens or through bystander damage [2]. A Phase I clinical trial is needed to determine the safety of EBV-specific adoptive immunotherapy in a larger number of patients with progressive MS. In view of the potential risk of aggravating CNS inflammation, this therapy should probably not be tried yet in patients with relapsing–remitting MS for which a number of disease-modifying therapies are already available.Another important question is how long any beneficial effect of EBV-specific adoptive immunotherapy in MS is likely to last. Because the therapy does not correct the generalized CD8+ T-cell deficiency that could underlie the impaired CD8+ T-cell immunity to EBV in MS [2,17], it is likely that EBV-specific CD8+ T-cell immunity may eventually wane again after the initial increase from immunotherapy. If such a decrease is accompanied by worsening of MS, consideration should be given to administering a further course of EBV-specific adoptive immunotherapy.The beneficial effect of EBV-specific adoptive immunotherapy in this first patient with progressive MS [16] provides supportive evidence for a pathogenic role of EBV, and of decreased CD8+ T-cell immunity to EBV, in the development of MS. In addition, our study has implications for the treatment of other chronic autoimmune diseases where EBV also has a pathogenic role [8].Financial & competing interests disclosureThe authors's study on Epstein–Barr virus-specific immunotherapy in the patient with progressive MS was supported by Multiple Sclerosis Research Australia, the Trish Multiple Sclerosis Research Foundation and the QIMR Rio-Tinto Flagship Program on Immunotherapy. MP Pender has no financial or competing interests. R Khanna holds a patent on the Epstein–Barr virus epitopes included in the AdE1-LMPpoly construct. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Ascherio A, Munger KL. Epstein–Barr virus infection and multiple sclerosis: a review. J. Neuroimmune Pharmacol. 5(3), 271–277 (2010).Crossref, Medline, Google Scholar2 Pender MP. The essential role of Epstein–Barr virus in the pathogenesis of multiple sclerosis. Neuroscientist 17(4), 351–367 (2011).Crossref, Medline, CAS, Google Scholar3 Pakpoor J, Disanto G, Gerber JE et al. The risk of developing multiple sclerosis in individuals seronegative for Epstein–Barr virus: a meta-analysis. Mult. Scler. 19(2), 162–166 (2013).Crossref, Medline, Google Scholar4 Levin LI, Munger KL, O'Reilly EJ, Falk KI, Ascherio A. Primary infection with the Epstein–Barr virus and risk of multiple sclerosis. Ann. Neurol. 67(6), 824–830 (2010).Medline, Google Scholar5 Sundström P, Juto P, Wadell G et al. An altered immune response to Epstein–Barr virus in multiple sclerosis: a prospective study. Neurology 62(12), 2277–2282 (2004).Crossref, Medline, CAS, Google Scholar6 Levin LI, Munger KL, Rubertone MV et al. Temporal relationship between elevation of Epstein–Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 293(20), 2496–2500 (2005).Crossref, Medline, CAS, Google Scholar7 Thacker EL, Mirzaei F, Ascherio A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann. Neurol. 59(3), 499–503 (2006).Crossref, Medline, Google Scholar8 Pender MP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol. 24(11), 584–588 (2003).Crossref, Medline, CAS, Google Scholar9 Serafini B, Rosicarelli B, Franciotta D et al. Dysregulated Epstein–Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204(12), 2899–2912 (2007).Crossref, Medline, CAS, Google Scholar10 Tzartos JS, Khan G, Vossenkamper A et al. Association of innate immune activation with latent Epstein–Barr virus in active MS lesions. Neurology 78(1), 15–23 (2012).Crossref, Medline, CAS, Google Scholar11 Hauser SL, Waubant E, Arnold DL et al. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N. Engl. J. Med. 358(7), 676–688 (2008).Crossref, Medline, CAS, Google Scholar12 Pender MP, Csurhes PA, Lenarczyk A, Pfluger CMM, Burrows SR. Decreased T cell reactivity to Epstein–Barr virus infected lymphoblastoid cell lines in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 80(5), 498–505 (2009).Crossref, Medline, CAS, Google Scholar13 Croia C, Serafini B, Bombardieri M et al. Epstein–Barr virus persistence and infection of autoreactive plasma cells in synovial lymphoid structures in rheumatoid arthritis. Ann. Rheum. Dis. 72(9), 1559–1568 (2013).Crossref, Medline, CAS, Google Scholar14 Smith C, Tsang J, Beagley L et al. Effective treatment of metastatic forms of Epstein–Barr virus-associated nasopharyngeal carcinoma with a novel adenovirus-based adoptive immunotherapy. Cancer Res. 72(5), 1116–1125 (2012).Crossref, Medline, CAS, Google Scholar15 Serafini B, Severa M, Columba-Cabezas S et al. Epstein–Barr virus latent infection and BAFF expression in B cells in the multiple sclerosis brain: implications for viral persistence and intrathecal B-cell activation. J. Neuropathol. Exp. Neurol. 69(7), 677–693 (2010).Crossref, Medline, CAS, Google Scholar16 Pender MP, Csurhes PA, Smith C et al. Epstein–Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis. Mult. Scler. doi:10.1177/1352458514521888 (2014) (Epub ahead of print).Crossref, Google Scholar17 Pender MP, Csurhes PA, Pfluger CMM, Burrows SR. Decreased CD8+ T cell response to Epstein–Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes. BMC Neurol. 11, 95 (2011).Crossref, Medline, CAS, Google Scholar18 Mancao C, Hammerschmidt W. Epstein–Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110(10), 3715–3721 (2007).Crossref, Medline, CAS, Google Scholar19 Rastelli J, Hömig-Hölzel C, Seagal J et al. LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1. Blood 111(3), 1448–1455 (2008).Crossref, Medline, CAS, Google Scholar20 Pender MP. Does Epstein–Barr virus infection in the brain drive the development of multiple sclerosis? Brain 132(12), 3196–3198 (2009).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByAdoptive T‐cell therapy targeting Epstein–Barr virus as a treatment for multiple sclerosis21 March 2023 | Clinical & Translational Immunology, Vol. 12, No. 3EBV transformation induces overexpression of hMSH2/3/6 on B lymphocytes and enhances γδT-cell-mediated cytotoxicity via TCR and NKG2D16 April 2018 | Immunology, Vol. 154, No. 4New advances in CNS immunity against viral infectionCurrent Opinion in Virology, Vol. 28CD8+ T-Cells as Immune Regulators of Multiple Sclerosis10 December 2015 | Frontiers in Immunology, Vol. 6Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy31 October 2014 | Clinical & Translational Immunology, Vol. 3, No. 10 Vol. 6, No. 6 STAY CONNECTED Metrics History Published online 21 July 2014 Published in print June 2014 Information© Future Medicine LtdKeywordsadoptive immunotherapyB cellCD8 T cellEpstein–Barr virusmultiple sclerosistreatmentFinancial & competing interests disclosureThe authors's study on Epstein–Barr virus-specific immunotherapy in the patient with progressive MS was supported by Multiple Sclerosis Research Australia, the Trish Multiple Sclerosis Research Foundation and the QIMR Rio-Tinto Flagship Program on Immunotherapy. MP Pender has no financial or competing interests. R Khanna holds a patent on the Epstein–Barr virus epitopes included in the AdE1-LMPpoly construct. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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