Doctor of Philosophy

dissertationB cell lymphoma is the most common hematologic malignancy with a relapsed setting of disease characterized by poor patient outcomes. The recent FDA approval of CD19-targeted CAR T cell therapy has offered a promising treatment option for patients with aggressive disease. However, many patients relapse from CD19 CAR T cell therapy, often with antigen negative disease, highlighting the need for additional targeted therapies as well as analysis of the mechanisms of relapse from currently available CAR treatments. Immune receptor CD229 is strongly expressed in the plasma cell malignancy multiple myeloma; however, whether CD229 is expressed in B cell malignancies that arise from B cells earlier in development remains unclear. Here, CD229 was found to be a highly expressed target antigen across numerous B cell lymphoma subtypes. Furthermore, CAR T cells targeting CD229 effectively lysed lymphoma cells in vitro and in vivo. Intriguingly, CD229 CAR T cells exhibit significantly reduced levels of target antigen loss by trogocytosis, a phenomenon describing the active transfer of surface molecules from one cell to another, compared to CD19 CAR T cells. Further investigation revealed CD19 CAR T cell mediated trogocytosis to be a rapid process that occurred with all subtypes of B cell lymphoma currently approved for CD19 CAR T cell therapy. Furthermore, transfer of the target antigen CD19 to CAR T cells directly resulted in fratricide and poor CAR T cell persistence. Finally, low affinity CAR T cells exhibited reduced antigen transfer by trogocytosis and enhanced expansion, providing rationale for the use of low affinity iv scFvs to improve CAR T cell persistence and anti-tumor efficacy in the clinic. In summary, this dissertation considers the gap in treatment for patients with relapsed B cell lymphoma through two independent means; first, through the development of CD229 CAR T cell therapy as a novel treatment option for patients with relapsed B cell lymphoma and second, through investigation of antigen loss by CAR T cell mediated trogocytosis and modulation of CAR affinity as an approach to address poor CAR T cell persistence and anti-tumor efficacy caused by trogocytosis