Multifactor mRNA Mediated T Cell Reprogramming for Systemic Lupus Erythematosus

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PROJECT SUMMARY Systemic Lupus Erythematosus (SLE) is a severe systemic autoimmune disease that leads to substantial morbidity and mortality in approximately 1 to 2 million Americans. A critical step in the pathogenesis of SLE is a breakdown in immune tolerance, which leads to a T-cell dependent and B-cell mediated disease. The resulting abundant pathogenic autoantibodies produced from the autoreactive B cells are a defining hallmark of SLE. The abrogation of disease in SLE-prone mice deficient in B cells, validates them as a viable therapeutic target. Indeed, several different B-cell directed therapies have been successful at attenuating progression including the anti-CD20 antibody Rituximab, and the anti-BAFF (BLyS) antibody belimumab – the first FDA approved drug for SLE in decades. Despite these exciting developments, the limited clinical response in only half of the treated patients, calls for further exploration of the extent and efficacy of B cell depletion. Overall the goal of this application is to optimize a B-cell targeted therapeutic intervention for SLE using CAR-T cells. Adoptive immunotherapy with genetically modified T cells expressing Chimeric Antigen Receptors (CARs) has shown remarkable therapeutic success in killing select cell populations. In particular, CARs that recognize CD19 have displayed impressive efficacy toward previously unresponsive B cell malignancies, and even plasma cell neoplasms. Here, we propose to employ our multiplexed mRNA-mediated T cell reprogramming technology to transiently eradicate aberrant, CD19-positive B cells. In comparison to antibodies, cellular immunotherapy has the advantages of active tissue penetration and no requirement for FcR-mediated uptake, which is blocked in SLE. In comparison to DNA reprogramming of T cells, an mRNA approach will permit a transient B cell depletion that can be deployed to match the relapsing-remitting nature of SLE. We will test the hypothesis that our mRNA approach will improve the functionality of the damaged SLE T cells by introducing mRNAs, coding multiple beneficial proteins in a single rapid step. Aim 1 will correct the propensity of SLE T cells to undergo apoptosis by reprogramming with a combination of mRNAs encoding an anti-apoptotic protein in addition to the CD19 CAR. Aim 2 will improve SLE T cell metabolic stability with an mRNA encoding a growth stimulatory cytokine that is diminished in SLE in addition to the CD19 CAR. Aim 3 will reprogram SLE T cells with the CD19 CAR and a chemokine receptor that will direct the CAR T cells to B cell rich areas. We will test these individual factors with complementary studies in early and established murine SLE as well as in lymphocytes from patients with SLE. Success of a CAR-T approach in SLE would be novel for autoimmune disease therapy and would lead to many potential opportunities for therapeutic exploration.