T cell receptor grafting allows virological control of Hepatitis B virus infection
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T cell receptor grafting allows virological control of Hepatitis B virus infection. / Wisskirchen, Karin; Kah, Janine; Malo, Antje; Asen, Theresa; Volz, Tassilo; Allweiss, Lena; Wettengel, Jochen M; Lütgehetmann, Marc; Urban, Stephan; Bauer, Tanja; Dandri, Maura; Protzer, Ulrike.
In: J CLIN INVEST, Vol. 129, No. 7, 30.04.2019, p. 2932-2945.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - T cell receptor grafting allows virological control of Hepatitis B virus infection
AU - Wisskirchen, Karin
AU - Kah, Janine
AU - Malo, Antje
AU - Asen, Theresa
AU - Volz, Tassilo
AU - Allweiss, Lena
AU - Wettengel, Jochen M
AU - Lütgehetmann, Marc
AU - Urban, Stephan
AU - Bauer, Tanja
AU - Dandri, Maura
AU - Protzer, Ulrike
PY - 2019/4/30
Y1 - 2019/4/30
N2 - T cell therapy is a promising means to treat chronic HBV infection and HBV-associated hepatocellular carcinoma. T cells engineered to express an HBV-specific T cell receptor (TCR) may achieve cure of 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 from chronic hepatitis B patients 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 4-5 log or below detection limit. When - as in a typical clinical setting - only a minority of hepatocytes were infected, engineered T cells specifically cleared infected hepatocytes without damaging non-infected cells. Cell death was compensated by hepatocyte proliferation and alanine amino transferase levels peaking at day 5 to 7 normalized again thereafter. Co-treatment 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.
AB - T cell therapy is a promising means to treat chronic HBV infection and HBV-associated hepatocellular carcinoma. T cells engineered to express an HBV-specific T cell receptor (TCR) may achieve cure of 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 from chronic hepatitis B patients 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 4-5 log or below detection limit. When - as in a typical clinical setting - only a minority of hepatocytes were infected, engineered T cells specifically cleared infected hepatocytes without damaging non-infected cells. Cell death was compensated by hepatocyte proliferation and alanine amino transferase levels peaking at day 5 to 7 normalized again thereafter. Co-treatment 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.
U2 - 10.1172/JCI120228
DO - 10.1172/JCI120228
M3 - SCORING: Journal article
C2 - 31039136
VL - 129
SP - 2932
EP - 2945
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 7
ER -
