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dc.contributor.authorSlabik, Constanze
dc.contributor.authorKalbarczyk, Maja
dc.contributor.authorDanisch, Simon
dc.contributor.authorZeidler, Reinhard
dc.contributor.authorKlawonn, Frank
dc.contributor.authorVolk, Valery
dc.contributor.authorKrönke, Nicole
dc.contributor.authorFeuerhake, Friedrich
dc.contributor.authorFerreira de Figueiredo, Constanca
dc.contributor.authorBlasczyk, Rainer
dc.contributor.authorOlbrich, Henning
dc.contributor.authorTheobald, Sebastian J
dc.contributor.authorSchneider, Andreas
dc.contributor.authorGanser, Arnold
dc.contributor.authorvon Kaisenberg, Constantin
dc.contributor.authorLienenklaus, Stefan
dc.contributor.authorBleich, Andre
dc.contributor.authorHammerschmidt, Wolfgang
dc.contributor.authorStripecke, Renata
dc.date.accessioned2020-09-25T11:33:08Z
dc.date.available2020-09-25T11:33:08Z
dc.date.issued2020-08-08
dc.identifier.citationMol Ther Oncolytics. 2020 Aug 8;18:504-524. doi: 10.1016/j.omto.2020.08.005.en_US
dc.identifier.issn2372-7705
dc.identifier.pmid32953984
dc.identifier.doi10.1016/j.omto.2020.08.005
dc.identifier.urihttp://hdl.handle.net/10033/622460
dc.description.abstractEpstein-Barr virus (EBV) is a latent and oncogenic human herpesvirus. Lytic viral protein expression plays an important role in EBV-associated malignancies. The EBV envelope glycoprotein 350 (gp350) is expressed abundantly during EBV lytic reactivation and sporadically on the surface of latently infected cells. Here we tested T cells expressing gp350-specific chimeric antigen receptors (CARs) containing scFvs derived from two novel gp350-binding, highly neutralizing monoclonal antibodies. The scFvs were fused to CD28/CD3ζ signaling domains in a retroviral vector. The produced gp350CAR-T cells specifically recognized and killed gp350+ 293T cells in vitro. The best-performing 7A1-gp350CAR-T cells were cytotoxic against the EBV+ B95-8 cell line, showing selectivity against gp350+ cells. Fully humanized Nod.Rag.Gamma mice transplanted with cord blood CD34+ cells and infected with the EBV/M81/fLuc lytic strain were monitored dynamically for viral spread. Infected mice recapitulated EBV-induced lymphoproliferation, tumor development, and systemic inflammation. We tested adoptive transfer of autologous CD8+gp350CAR-T cells administered protectively or therapeutically. After gp350CAR-T cell therapy, 75% of mice controlled or reduced EBV spread and showed lower frequencies of EBER+ B cell malignant lymphoproliferation, lack of tumor development, and reduced inflammation. In summary, CD8+gp350CAR-T cells showed proof-of-concept preclinical efficacy against impending EBV+ lymphoproliferation and lymphomagenesis.en_US
dc.language.isoenen_US
dc.publisherElsevier (Cell Press)en_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectCAR-T cellsen_US
dc.subjectEBVen_US
dc.subjectPTLDen_US
dc.subjectadoptive T cell therapyen_US
dc.subjectgp350en_US
dc.subjecthumanized miceen_US
dc.subjectlymphomaen_US
dc.subjectlymphoproliferationen_US
dc.subjectlytic infectionen_US
dc.subjecttransplantationen_US
dc.titleCAR-T Cells Targeting Epstein-Barr Virus gp350 Validated in a Humanized Mouse Model of EBV Infection and Lymphoproliferative Disease.en_US
dc.typeArticleen_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalMolecular therapy oncolyticsen_US
dc.source.volume18
dc.source.beginpage504
dc.source.endpage524
refterms.dateFOA2020-09-25T11:33:09Z
dc.source.journaltitleMolecular therapy oncolytics
dc.source.countryUnited States


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Attribution-NonCommercial-ShareAlike 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International