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Festag, J. ; Festag, M.M.* ; Asen, T. ; Wettengel, J.* ; Mück-Häusl, M. ; Abdulhaqq, S.* ; Stahl-Hennig, C.* ; Sacha, J.* ; Burwitz, B.* ; Protzer, U. ; Wisskirchen, K.

Vector-mediated delivery of human MHC-I into hepatocytes enables investigation of TCR-redirected HBV-specific T cells in mice and macaque cell cultures.

Hum. Gene Ther. 34, 1204-1218 (2023)
DOI PMC
Adoptive T-cell therapy using natural T-cell receptor (TCR) redirection is a promising approach to fight solid cancers and viral infections in liver and other organs. However, clinical efficacy of such TCR+-T cells has been limited so far. One reason is that syngeneic preclinical models to evaluate safety and efficacy of TCR+-T cells are missing. We therefore developed an efficient viral vector strategy mediating expression of human MHC-I in hepatocytes, which allows evaluation of TCR-T cell therapies targeting diseased liver cells. We designed adeno-associated virus (AAV) and adenoviral vectors encoding either the human-mouse chimeric HLA-A*02-like molecule HHD, or fully human HLA-A*02 and human 2 microglobulin (h2m). Upon transduction of murine hepatocytes, the HLA-A*02 construct proved superior in terms of expression levels, presentation of endogenously processed peptides and activation of murine TCR+-T cells grafted with HLA-A*02-restricted, hepatitis B virus (HBV)-specific TCRs. In vivo, these T cells elicited effector function, controlled HBV replication, reduced HBV viral load and antigen expression specifically in livers of mice that had received AAV-HBV and AAV-HLA-A*02. We then demonstrated the utility of this approach by expressing the HBV-specific TCRs on macaque primary T cells enabling them to recognize HBV-infected macaque hepatocytes expressing HLA-A*02 upon adenoviral transduction. In conclusion, AAV and adenovirus vectors are suitable for delivery of HLA-A*02 and h2m into mouse and macaque hepatocytes. When recognizing HBV in the HLA-A*02-transduced mouse livers or on macaque hepatocytes, HLA-A*02-restricted, HBV-specific TCR+-T cells become activated and exert antiviral effector functions. This approach is applicable to other MHC restrictions and target diseases, paving the way for safety and efficacy studies of human TCR-based therapies in physiologically relevant preclinical animal models.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Aav Vector ; Adoptive T Cell Therapy ; Hepatitis B Virus ; Hla-a*02 ; Mhc-i Molecule ; Primary Macaque Hepatocytes ; Primary Mouse Hepatocytes; Chimeric Antigen Receptor; Immune-response; Surface-antigen; Replication; Expression; System; Safety; Model; Hbv
ISSN (print) / ISBN 1043-0342
e-ISSN 1557-7422
Zeitschrift Human Gene Therapy. Clinical Development
Quellenangaben Band: 34, Heft: 23-24, Seiten: 1204-1218 Artikelnummer: , Supplement: ,
Verlag Mary Ann Liebert
Verlagsort 140 Huguenot Street, 3rd Fl, New Rochelle, Ny 10801 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Förderungen National Institutes of Health
TUM Graduate School
Young investigator
German Center for Infection Research (DZIF), TTU Hepatitis
German Research Foundation (DFG)