PuSH - Publication Server of Helmholtz Zentrum München: Vector-mediated delivery of human MHC-I into hepatocytes enables investigation of TCR-redirected HBV-specific T cells in mice and macaque cell cultures.

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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)

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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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