Author(s): Chloe Kang, Abigail Cheever, Hunter Lindsay, Kimball Demars
Mentor(s): K. Scott Weber, Kim O'Neill
Institution BYU
Chimeric antigen receptor (CAR) T cells have had significant impacts in treating hematological cancers by eliminating B cells using an anti-CD19 domain and have recently shown similar success in treating B-cell mediated autoimmune diseases. Graves’ Disease (GD) is a B cell-mediated autoimmune disease of the thyroid, where autoreactive B cells produce autoantibodies which bind to thyroid stimulating hormone receptor (TSHR). Current treatments of GD fail to target the source of the disease, autoreactive B cells, and rather administer radioiodine therapy or remove the thyroid entirely. GD has also been associated with the development of thyroid cancer, and radioiodine therapy has been shown to lead to an increased risk of leukemias and lymphomas. We have created chimeric autoantigen receptor (CAAR) T cells, which target autoreactive B cells in GD, by creating a novel receptor with TSHR as the binding domain. Though we have shown these CAAR T cells successfully eliminate the autoreactive B cells in GD, soluble autoantibodies and TSH can impede CAR T cell efficacy to a degree. The novel LINK CAR system increases specificity by requiring binding at two domains to activate T cell cytotoxicity. We developed a LINK CAAR T cell by inserting both an anti-CD19 scFv and a TSHR as binding domains. Using CRISPR gene editing to create B cell controls, we have started initial tests of the binding and cytotoxicity of our LINK CAAR T cells. Cytotoxicity assays have shown that the LINK CAR T cells are only activated to kill when both receptors are bound to one cell. As a safer treatment with heightened specificity, LINK CAR T cell therapy has promising applications for GD and many other autoimmune diseases.