Systemic lupus erythematosus (SLE) is an autoimmune disease that impacts over 3 million people, causing joint pain, organ damage, and impaired quality of life. Existing SLE drugs are non-specific and cause side effects. With NIAID Fast-Track U44 support, we will test a new cell therapy technology as a safe and potent treatment for SLE. The goal of chimeric antigen receptor T cell (CAR-T) therapy is to eliminate pathogenic cells by engineering CARs to bind antigens on a target cell. This involves isolation and engineering of patient T cells to express CAR, followed by reinfusion. All approved CAR-T therapies rely on transfection of T cells with DNA that permanently modifies the genome and requires proliferation for efficacy. For these cells to thrive and expand, patients must first be admitted to the hospital to receive preconditioning chemotherapy. Beyond these burdens, permanent CAR expression resulting from DNA engineering causes unconstrained proliferation and toxicity that drive costs as high as $2.0M. These hurdles have limited CAR-T cell treatment only to advanced refractory cancers. We have designed a new approach for CAR-T using RNA to achieve transient CAR expression (rCAR-T). These cells do not require proliferation, instead relying on rapid depletion of target cells as CAR expression decays during cell division. This feature limits toxicity, eliminating preconditioning chemotherapy and inpatient stays. Thus, rCAR-T creates a unique opportunity to expand cell therapy to autoimmunity. We have engineered cells with rCAR-T to bind B cell maturation antigen (BCMA), an antigen on the plasma cells (PCs) that secrete the pathogenic autoantibodies characteristic of many autoimmune diseases. This therapy – “Descartes-08” – transiently expresses anti-BCMA CAR to eliminate BCMA+ PCs after infusion without inducing serious toxicity. In a Phase 2a trial (NCT04146051), Descartes- 08 conferred potent, safe, and long-lasting improvement in patients with Myasthenia Gravis, an autoantibody associated autoimmune disorder (AAAD) in which PCs produce autoantibodies targeting neuromuscular junctions. Since BCMA+ PCs also produce the autoantibodies that attack ubiquitous nuclear antigens in SLE, here we will test if Descartes-08 provides safe, effective, and durable treatment of SLE. In July 2023 the FDA allowed our IND for SLE; we have initiated a Phase 2a open label trial in patients with SLE (NCT06038474). In SBIR Phase 1, we will use data from this trial to finalize design of a randomized, placebo-controlled Phase 2b trial (RCT) for SLE that will be executed in SBIR Phase 2. The aims are: i) Finalize the design and operating procedures for the Phase 2b Descartes-08 RCT in SLE, ii) Show Descartes-08 drives clinical benefit, reduced autoantibodies, & phenotypic changes in RCT, and iii) Show the safety and tolerability of Descartes-08 in patients with SLE during the Phase 2b RCT. This plan is aligned with the U44 Cooperative Mechanism requirements because De...