GENETIC ENGINEERING OF T CELLS FOR THE TARGETED THERAPY OF PRIMARY BILIARY CHOLANGITIS

Abstract

Primary Biliary Cholangitis (PBC) is a life-threatening liver autoimmune disease, with increasing prevalence worldwide. They are problematic to control because of the complex nature of the disease processes. B cells are a type of immune cells and are one of the major cell types involved in disease causation and progression. Therefore, B cells have been targeted in the treatment using depleting antibodies but have achieved unsatisfactory outcomes due to complete depletion of B cells instead disease-causing ones. Furthermore, pan B cell depletion using depleting antibodies requires repeated administration and associated with systemic humoral immune suppression. Hence, approaches that address these limitations yet kill only disease-causing B cells represent as a best approach to treat PBC. The hypothesis is that killing these disease-causing B cells will ameliorate disease pathology. In my project, I aimed to target and kill disease causing B cells in PBC. Firstly, the CD19 CAR T cells were generated and evaluated for their therapeutic efficacy through whole B cell depletion in the murine model of PBC. Later, the disease/antigen specific PDC CAAR T cells were generated and evaluated in vitro and in vivo. To do this, the T cells are genetically engineered to express PBC disease relevant autoantigen E2 component of Pyruvate dehydrogenase complex (PDC-E2) on their surface such that they recognize only disease-causing B cells via surface autoantibodies. Then, we evaluated whether these T cells efficient in killing autoreactive B cells using in vitro bioassays and in vivo murine model of PBC. Both the CD19 CAR T cells and PDC CAAR T cells have shown their therapeutic effect on the gross pathology, histopathology and serological readouts of liver damage in the PBC model. Through this project, we developed and successfully tested promising therapeutic drugs preclinically, establishing proof-of-concept for in-depth mechanistic and translational studies. Ultimately, our work paves the way for these drugs to treat human PBC, benefiting our healthcare system and enhancing Canada's innovation and commercialization landscape.