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Slabik, C.* ; Kalbarczyk, M.* ; Danisch, S.* ; Zeidler, R. ; Klawonn, F.* ; Volk, V.* ; Krönke, N.* ; Feuerhake, F.* ; Ferreira de Figueiredo, C.* ; Blasczyk, R.* ; Olbrich, H.* ; Theobald, S.J.* ; Schneider, A.* ; Ganser, A.* ; von Kaisenberg, C.* ; Lienenklaus, S.* ; Bleich, A.* ; Hammerschmidt, W. ; Stripecke, R.*

CAR-T cells targeting Epstein-Barr virus gp350 validated in a humanized mouse model of EBV infection and lymphoproliferative disease.

Mol. Ther.-Oncolytics 18, 504-524 (2020)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Epstein-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/CD zeta 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, CDegp350CAR-T cells showed proof-of-concept preclinical efficacy against impending EBV+ lymphoproliferation and lymphomagenesis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Adoptive T Cell Therapy ; Car-t Cells ; Ebv ; Gp350 ; Humanized Mice ; Lymphoma ; Lymphoproliferation ; Lytic Infection ; Ptld ; Transplantation; Chimeric Antigen Receptor; In-vitro; Monoclonal-antibody; Viral-infections; Mice; Immunotherapy; Glycoprotein; Multicenter; Expression; Lymphoma
ISSN (print) / ISBN 2372-7705
e-ISSN 2372-7705
Zeitschrift Molecular Therapy-Oncolytics
Quellenangaben Band: 18, Heft: , Seiten: 504-524 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Gene Vector (AGV)
Förderungen JACKSON LABORATORY
German Research Council
German Research Council (DFG/REBIRTH Unit 6.4)
DAAD/ZIB Ph.D. fellowship
RegSci PhD fellowship
REBIRTH Unit 6.3
German Ministry of Education and Research (BMBF)
DLR project management (e:Med) grants
German Center for Infections Research