T cell receptor grafting allows virological control of hepatitis B virus infection
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 safe...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
June 10, 2019
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| In: |
The journal of clinical investigation
Year: 2019, Volume: 129, Issue: 7, Pages: 2932-2945 |
| ISSN: | 1558-8238 |
| DOI: | 10.1172/JCI120228 |
| Online Access: | Resolving-System, Volltext: http://dx.doi.org/10.1172/JCI120228 Verlag, Volltext: https://www.jci.org/articles/view/120228 
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| Author Notes: | Karin Wisskirchen, Janine Kah, Antje Malo, Theresa Asen, Tassilo Volz, Lena Allweiss, Jochen M. Wettengel, Marc Luetgehetmann, Stephan Urban, Tanja Bauer, Maura Dandri, and Ulrike Protzer |
| Summary: | 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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| Item Description: | Gesehen am 20.08.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1558-8238 |
| DOI: | 10.1172/JCI120228 |