Author(s): Kimball Demars, Abigail Cheever, Hunter Lindsay, Chloe Kang
Mentor(s): K. Scott Weber, Kim O'Neill
Institution BYU
Graves’ Disease (GD) is a B cell-mediated autoimmune disease where some B cells become autoreactive, releasing autoantibodies that bind to thyroid stimulating hormone receptor (TSHR) on thyroid cells and trigger the unnecessary release of hormones. Current treatments include radioiodine therapy, antithyroid drugs, or a thyroidectomy, but they all fail to target the source of GD: the autoreactive B cells. However, recent advancements in a novel cancer treatment can be adapted for a GD treatment that is both safe and long-lasting. This treatment, namely chimeric autoantigen receptor (CAAR) T cell therapy, places TSHR as the binding domain of the CAAR T cell, allowing it to bind specifically to autoreactive GD B cells. TSHR was modeled with AlphaFold2 to determine which epitopes would most effectively bind to anti-TSHR autoantibodies, and they were cloned into a CAR construct. Over a 72 hour period, the CAAR T cells, CAAR 2 and CAAR 2.7 were coincubated with engineered anti-TSHR B cell lines, and both CAARs displayed elimination of GD B cells while releasing expected amounts of proinflammatory cytokines. Additionally, both CAAR epitopes did not kill healthy B cells or release proinflammatory cytokines in their presence. We also evaluated whether soluble autoantibodies and TSH would have an affect on the efficacy of our CAAR T cells. There were some effects to killing rate and cytokine production, with more pronounced effects on CAAR 2.7. The CAAR T cells were also tested in the presence of GF patient serum, and autoreactive B cells were still effectively eliminated. CAAR T cell therapy shows promise in treatment of GD, and could have potential in the treatment of other B cell-mediated autoimmune diseases.