Development Of Genetically Engineered Tcr-Transduced T Cells For Immunotherapy Of Chronic Hepatitis B And C Virus Infections

Abstract More than 350 million people worldwide are chronically infected with hepatitis B (HBV) or hepatitis C virus (HCV). While vigorous CD8 T cell responses are required to spontaneously clear acute HBV and HCV infections, these virus-specific T cells are typically diminished in number and functionally impaired in chronic HBV and HCV infections. Here, we set out to use adoptive therapy with TCR-engineered T cells to restore HBV and HCV-specific immune responses. Three HBV-specific and four HCV-specific TCRs with high avidity were cloned from patients and chimpanzees that cleared the respective infection, expressed in retroviral vectors and used to transduce lymphocytes of chimpanzees with chronic HBV and HCV infection. The transduced T cells gained a broad spectrum of antigen-specific effector functions (IFN-γ secretion, cytotoxicity and proliferation). They were expanded to high numbers via short-term anti-CD3 and IL-15/IL-21 stimulation, which resulted in a preservation of their differentiation status and a lower frequency of regulatory T cells than the conventional expansion method with anti-CD3 and IL-2. Collectively, we show that retroviral TCR gene transfer followed by short-term expansion in the presence of IL-15/IL-21 efficiently redirects the antigen specificity of resting primary T cells and generates a large number of functional effector T cells. These will be used in adoptive T cell therapy protocols to restore T cell function in chronic viral hepatitis.