T cell receptor grafting allows virological control of hepatitis B virus infection
Karin Wisskirchen, Janine Kah, Antje Malo, Theresa Asen, Tassilo Volz, Lena Allweiss, Jochen M. Wettengel, Marc Lütgehetmann, Stephan Urban, Tanja Bauer, Maura Dandri, Ulrike Protzer
Karin Wisskirchen, Janine Kah, Antje Malo, Theresa Asen, Tassilo Volz, Lena Allweiss, Jochen M. Wettengel, Marc Lütgehetmann, Stephan Urban, Tanja Bauer, Maura Dandri, Ulrike Protzer
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Research Article Immunology Virology

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

Abstract

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.

Authors

Karin Wisskirchen, Janine Kah, Antje Malo, Theresa Asen, Tassilo Volz, Lena Allweiss, Jochen M. Wettengel, Marc Lütgehetmann, Stephan Urban, Tanja Bauer, Maura Dandri, Ulrike Protzer

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Figure 6

In situ analysis of antiviral effects of TCR-grafted T cells in humanized livers.

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In situ analysis of antiviral effects of TCR-grafted T cells in humanize...
Liver tissue from HBV-infected mice treated with mock-transduced T cells or 2 × 106 HBV-specific T cells (1 × 106 with 6KC18 plus 1 × 106 with 4GS20) were used from days 18–19 (short-term follow-up) or day 55 after T cell transfer (long-term follow-up). (A) RNA in situ hybridization for HBV pgRNA (green) and human β2-microglobulin (magenta) against nuclei staining (blue) was performed to determine the occurrence of HBV-specific RNA transcripts. (B) As indicated, mice were categorized as having a high (109 to 1010 copies/ml) or low (107 to 108 copies/ml) HBV titer. Representative immunohistochemical staining for cell nuclei (blue), HBV core protein (green), and human CK18 (hCK18) (red). (C) Human CD45+ cells (green) were stained against human calnexin (hCalnexin) (red) as a marker for human hepatocytes and cell nuclei (blue). (D) To determine potential proliferation in mice treated with T cells, staining for cell nuclei (blue), human CK18 (green), and human Ki67 (hKi67) (red) was done. Scale bars: 50 μm.