CAR-T Cells Targeting Epstein-Barr Virus gp350 Validated in a Humanized Mouse Model of EBV Infection and Lymphoproliferative Disease
| Autor: | Friedrich Feuerhake, Arnold Ganser, Constantin von Kaisenberg, Nicole Krönke, Reinhard Zeidler, Constanca Figueiredo, Constanze Slabik, Wolfgang Hammerschmidt, Henning Olbrich, Rainer Blasczyk, André Bleich, Valery Volk, Frank Klawonn, Stefan Lienenklaus, Sebastian J. Theobald, Maja Kalbarczyk, Simon Danisch, Renata Stripecke, Andreas Schneider |
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| Přispěvatelé: | HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Adoptive cell transfer lymphoproliferation CAR-T cells adoptive T cell therapy lymphoma Biology medicine.disease_cause lcsh:RC254-282 Viral vector gp350 03 medical and health sciences 0302 clinical medicine EBV hemic and lymphatic diseases medicine Cytotoxic T cell Pharmacology (medical) B cell lytic infection lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Epstein–Barr virus Virology Chimeric antigen receptor 030104 developmental biology medicine.anatomical_structure PTLD humanized mice Oncology Lytic cycle Adoptive T Cell Therapy Car-t Cells Ebv Gp350 Humanized Mice Lymphoma Lymphoproliferation Lytic Infection Ptld Transplantation 030220 oncology & carcinogenesis Humanized mouse Molecular Medicine Original Article transplantation |
| Zdroj: | Molecular Therapy: Oncolytics, Vol 18, Iss, Pp 504-524 (2020) Molecular Therapy Oncolytics Mol. Ther.-Oncolytics 18, 504-524 (2020) Molecular therapy oncolytics United States |
| ISSN: | 2372-7705 |
| Popis: | 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. Graphical Abstract EBV is an oncogenic virus, and lytic infection has been shown to promote malignancies. Slabik et al. showed that CAR-T cells targeting the gp350 envelope protein can react against EBV-infected cells. Humanized mice infected with EBV and treated with gp350CAR-T cells controlled EBV spread and EBV+ lymphoproliferative disease. |
| Databáze: | OpenAIRE |
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