Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can lead to severe organ damage, including kidney failure. Current treatments targeting B cells, such as belimumab (Benlysta), have shown promise but are not curative. Recent studies using CD19-targeted chimeric antigen receptor (CAR) T cell therapy have shown that clearing B cells can lead to remission (decrease or absence of symptoms) in SLE. However, long-lived B cells called plasma cells, which can produce harmful antibodies, do not express CD19, making it difficult to achieve remission. Dr. Parameswaran is developing a new treatment using chimeric antigen receptor-natural killer (CAR-NK) cells that target molecules called BAFFR, TACI, and BCMA on self-reactive B cells (those that recognize the patient’s own body), including long-lived plasma cells.

Natural killer (NK) cells are a type of white blood cell that plays a crucial role in the body’s immune response by targeting and destroying infected or cancerous cells. Dr. Parameswaran’s approach involves using CAR-NK cells generated from healthy donors as an “off-the-shelf” therapy, which reduces costs and increases safety. Preliminary data shows that these BAFF CAR-NK cells can effectively eliminate self-reactive B cells in both mouse models and human lupus patient samples. The study will evaluate the effectiveness and safety of BAFF CAR-NK cells in three stages: testing their ability to kill lupus patient B cells in the lab, assessing their therapeutic efficacy in mouse models of lupus, and determining the optimal dosage and safety in humanized mouse models. If successful, this research could lead to a new, effective treatment for SLE.

What this means for people with lupus

Dr. Parameswaran’s research could lead to a new, cost-effective therapy that targets harmful B cells more precisely, potentially leading to long-term remission in lupus patients. This innovative approach could improve treatment outcomes and quality of life for people with lupus.

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. Recent studies using CD19 Chimeric antigen receptor (CAR) T cell therapy indicates B cell clearance leads to SLE disease remission. But, long-lived plasma cells which produce autoreactive antibodies do not express CD19. We thus seek to circumvent this issue in a new treatment for SLE using a BAFF-ligand based CAR-NK cell product. The BAFF receptors BAFFR, TACI, and BCMA are expressed on autoreactive B cells and 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 will lead to long term remission in SLE patients. We propose to use CAR-NK cells generated from random healthy donors as an “off the shelf” therapy, which reduces cost and increases safety of this therapy. Our preliminary data confirms the feasibility to generate mouse and human BAFF CAR-T cells and it’s efficacy in eliminating mouse and human autoreactive B cells in both syngeneic mouse lupus models and from lupus patient’s peripheral blood respectively. CAR-NK cells has many advantages over CAR-T cells including no dangerous cytokine release and no graft versus host effect, which makes “off the shelf” therapy possible. To analyze the long-term therapeutic efficacy of BAFF CAR-NK cells in the context of SLE, we propose three complementary aims that will assess Aim1: In vitro evaluation of cytotoxicity of BAFF CAR-NK cells on lupus patient B cells, Aim2: In vivo evaluation of therapeutic efficacy of BAFF CAR-NK in Syngenic mouse models of lupus and Aim3: In vivo evaluation of BAFF CAR-NK dosage and safety in humanized mouse models of lupus. We hope to advancing this technology to clinic after performing these IND-enabling studies.