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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)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords 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
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 2372-7705
e-ISSN 2372-7705
Journal Molecular Therapy-Oncolytics
Quellenangaben Volume: 18, Issue: , Pages: 504-524 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
PSP Element(s) G-501501-001
G-501500-001
Grants 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
DOI 10.1016/j.omto.2020.08.005
WOS ID WOS:000575168700042
Scopus ID 85090110848
PubMed ID 32953984
Erfassungsdatum 2020-10-26
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