Characterization and Optimization of a Murine Engineered CAR T cell Surrogate for the Treatment of Autoimmune and Autoinflammatory Conditions

Abstract

The adaptive immune system can occasionally generate cells that are autoreactive, leading them to trigger autoimmune responses led by diminishing function or numbers of Tregs. Regulatory T cells (Tregs) are a rare subpopulation of T cells that play a critical role in the maintenance of homeostasis and immune tolerance. While Chimeric Antigen Receptor (CAR) T cell therapy is already an important therapeutic modality for tackling complex autoimmune conditions, the generation of a CAR Treg may prove more effective and specific, treating the autoimmune condition more directly without the off target toxicity effects. This thesis evaluates preclinical surrogates for CD19 CAR T cells which, following optimization, were compared to CD19 CAR Tregs in a murine inflammatory model in terms of safety, engraftment, off-target effects, and efficacy. Following optimization, the newly engineered CAR T cell was an effective control tested in co-culture assays with B cells and T cells, showcasing the off-target immune response that was not observed with the specific CAR Treg cultures. In an in vivo model of systemic lupus erythematosus, CAR T cells generated a significant immune response compared to the CAR Tregs. This suggests that a specific CAR Treg would be a safer alternative to a CAR T cell-based therapy.