Allogeneic BAFF Ligand Based CAR T-Cells as a Novel Therapy for Systemic Lupus Erythematous - Abstract
Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease with no cure
which affects 1.5 million Americans. SLE is a rheumatic disease which can lead to severe organ
dysfunction, including end stage renal disease. Autoreactive B cells have emerged as primary
drivers of the disease and the presence of anti-nuclear antibodies is a biomarker for diagnosis.
Therapies targeting B cells and the B cell activating factor (BAFF) signaling axis, including
belimumab, a monoclonal antibody targeting BAFF, have shown promising results in reducing
severity of disease in B cell associated autoimmunity, but these treatments are not curative. A
recent studying using CD19 Chimeric antigen receptor (CAR) T cell therapy led to B cell
clearance and disease remission in 4 of 5 patients. Each of these patients were in early-stage
lupus, but the one who did not respond had the longest-term disease at 9 years. This study
indicates B cell clearance can resolve SLE disease progression, but the CD19-CAR treatment
was limited in targeting all the autoreactive B cells, including long-lived plasma cells which
produce autoreactive antibody but do not express CD19. We thus seek to circumvent this issue
in a new treatment for SLE using an allogeneic BAFF-ligand based CAR γδ T cell product.
The BAFF family receptors BAFFR, TACI, and BCMA are highly expressed on B cells at
different proportions depending on their maturation state including plasma cells. We
hypothesize that elimination of all autoreactive B cells, including long-lived plasma cells in the
bone marrow, will reduce the production of autoantibodies and lead to long term remission. The
use of γδ T cells allows for the mass production of allogeneic CAR T cells from a single T cell
donor, reducing cost and increasing safety oversight during manufacturing. We have produced
preliminary data that confirms our ability to use the non-viral TcBuster DNA transposon system
to generate γδ T cells with BAFF-CAR expression and show that these cells are effective at
eliminating cells expressing the BAFF family of receptors. To test the efficacy of the CAR in the
context of SLE, we propose two complementary aims that will assess the expression of BAFF
receptors in SLE patient B cells and test the activity and selectivity of these cells against patient
B cells in vitro. Finally, we will test the efficacy of the BAFF-CAR γδ T cells in reducing
inflammation, renal disease, and autoantibody production in a humanized mouse model of SLE.
We hope to improve outcomes in SLE by advancing this technology to IND-enabling studies.
