TY  - JOUR
AB  - 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.
AU  - Slabik, C.*
AU  - Kalbarczyk, M.*
AU  - Danisch, S.*
AU  - Zeidler, R.
AU  - Klawonn, F.*
AU  - Volk, V.*
AU  - Krönke, N.*
AU  - Feuerhake, F.*
AU  - Ferreira de Figueiredo, C.*
AU  - Blasczyk, R.*
AU  - Olbrich, H.*
AU  - Theobald, S.J.*
AU  - Schneider, A.*
AU  - Ganser, A.*
AU  - von Kaisenberg, C.*
AU  - Lienenklaus, S.*
AU  - Bleich, A.*
AU  - Hammerschmidt, W.
AU  - Stripecke, R.*
C1  - 60014
C2  - 49165
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 504-524
TI  - CAR-T cells targeting Epstein-Barr virus gp350 validated in a humanized mouse model of EBV infection and lymphoproliferative disease.
JO  - Mol. Ther.-Oncolytics
VL  - 18
PB  - Cell Press
PY  - 2020
SN  - 2372-7705
ER  -