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Wisskirchen, K. ; Kah, J.* ; Malo, A. ; Asen, T. ; Volz, T.* ; Allweiss, L.* ; Wettengel, J.M.* ; Lütgehetmann, M.* ; Urban, S.* ; Bauer, T. ; Dandri, M.* ; Protzer, U.

T cell receptor grafting allows virological control of hepatitis B virus infection.

J. Clin. Invest. 130, 2932-2945 (2019)
Verlagsversion Postprint Forschungsdaten DOI PMC
Open Access Green
T cell therapy is a promising means to treat chronic hepatitis B virus (HBV) infection and HBV-associated hepatocellular carcinoma. T cells engineered to express an HBV-specific T cell receptor (TCR) may cure an HBV infection upon adoptive transfer. We investigated the therapeutic potential and safety of T cells stably expressing high-affinity HBV envelope- or core-specific TCRs recognizing European and Asian HLA-A2 subtypes. Both CD8(+) and CD4(+) T cells from healthy donors and patients with chronic hepatitis B became polyfunctional effector cells when grafted with HBV-specific TCRs and eliminated HBV from infected HepG2-NTCP cell cultures. A single transfer of TCR-grafted T cells into HBV-infected, humanized mice controlled HBV infection, and virological markers declined by 4 to 5 log or below the detection limit. Engineered T cells specifically cleared infected hepatocytes without damaging noninfected cells when, as in a typical clinical setting, only a minority of hepatocytes were infected. Cell death was compensated by hepatocyte proliferation, and alanine amino transferase levels peaking between days 5 and 7 normalized again thereafter. Cotreatment with the entry inhibitor myrcludex B ensured long-term control of HBV infection. Thus, T cells stably transduced with highly functional TCRs have the potential to mediate clearance of HBV-infected cells, causing limited liver injury.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Hepatitis ; Immunology ; Immunotherapy ; T Cells ; Virology; Chimeric Antigen Receptor; Humanized Mice; Cancer Regression; Adoptive Transfer; Viral Clearance; Immunity; Cd8(+); Replication; Hepatocytes; Expression
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: 130, Heft: 7, Seiten: 2932-2945 Artikelnummer: , Supplement: ,
Verlag American Society of Clinical Investigation
Verlagsort 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)