Overcoming barriers for T cell therapy of hepatitis B and hepatocellular carcinoma
Virology, Immune Therapy, Virus-induced Cancer
Hepatitis B virus (HBV) can be controlled by natural T cell immunity, but this control fails in chronic infection causing liver disease and cancer. T cells expressing CARs or TCRs can be specifically redirected to HBV-positive hepatocytes and cancer cells. Our long-term goal is to establish T cell therapy as a means of treatment to eliminate hepatocytes persistently infected with HBV and in particular those that carry HBV integrates and serve as precursors of liver cancer development.
HBV has evolved to escape sterilizing immune responses by evading T cell immunity, and HBV-associated HCC takes advantage of this. HBV resides in the liver providing an environment that tends to turn-off T cell effector function and its host cell, the hepatocyte, is characterized by low MHC expression. The high amount of HBV antigens expressed in hepatocytes and secreted into the circulation seem to contribute to immune evasion. The first aim of this project is to determine whether lowering the number of target cells or the antigen load or altering the site of antigen encounter will improve effector function of CAR- and TCR-grafted T cells and whether additional means to engineer T cells of improved function will be required. If HBV is controlled by endogenous immune responses, a broad and polyclonal CD4 and CD8 T cell response is observed. To mimic such a response by engineered T cells is currently not possible because clinical development of such a combination is too complicated. Therefore, either a single, optimal TCR will be required or a combination of a few TCRs ideally directed against different viral antigens. The second aim is this project is therefore to identify the optimally suited TCRs. To achieve this, we will expand our TCR library to TCRs recognizing non-structural HBV proteins and use TCR-retrogenic mice harboring a spectrum of preselected HLA- A2 restricted TCRs and infect them with an adenoviral vector expressing HLA-A2 and inducing HBV replication to define TCR hierarchies.
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