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CAR-T Cells Targeting Epstein-Barr Virus gp350 Validated in a Humanized Mouse Model of EBV Infection and Lymphoproliferative Disease.
Slabik, Constanze Kalbarczyk, Maja Danisch, Simon Zeidler, Reinhard Volk, Valery Krönke, Nicole Feuerhake, Friedrich Ferreira de Figueiredo, Constanca Blasczyk, Rainer
Slabik, Constanze
Kalbarczyk, Maja
Danisch, Simon
Zeidler, Reinhard
Volk, Valery
Krönke, Nicole
Feuerhake, Friedrich
Ferreira de Figueiredo, Constanca
Blasczyk, Rainer
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2020-08-08
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Abstract
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/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.
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Mol Ther Oncolytics. 2020 Aug 8;18:504-524. doi: 10.1016/j.omto.2020.08.005.
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en
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2372-7705
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Attribution-NonCommercial-ShareAlike 4.0 International