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Objectives The goal of current therapies for SLE is to control disease activity, reduce organ damage, and decrease long-term morbidity/mortality. Therapies providing durable clinical responses without requiring chronic immunosuppressive drugs are lacking. Rese-cel is an investigational, fully human, autologous 4-1BB CD19-CAR T cell therapy, designed to deeply and transiently deplete CD19 + B cells following a single weight-based infusion, potentially enabling an ‘immune reset’ with durable responses. RESET-SLE ( NCT06121297) is a Phase 1/2 trial evaluating the safety and efficacy of rese-cel in 2 independent cohorts of non-renal SLE and LN.Methods Eligible patients are 18-65 years old with SLE, ANA+/anti-dsDNA+, and SLEDAI 2K =/>8 (non-renal SLE cohort), or active, biopsy-confirmed class III/IV ± V LN (LN cohort), despite standard of care. A single rese-cell infusion (1x10e6 cells/kg) is administered following standard preconditioning. All non-glucocorticoid immunomodulatory agents are discontinued by preconditioning; glucocorticoids are subsequently tapered.Adverse events, SLE medication, disease activity and translational end points are assessed.Results As of June 2025, 8 patients (4 per cohort) have received rese-cel and completed =/>1 month follow-up ( table 1A). Grade 1 CRS was reported in 2 patients and Grade 4 ICANS in 1 patient; associated with a potential occult infection, which rapidly resolved following standard management.The 7 evaluable patients have experienced clinical improvement; the 8th patient had insufficient follow-up. In the non-renal SLE cohort, 3 patients achieved DORIS at latest follow-up, the 4th patient (with class V LN), achieved DORIS at Week 48; CRR at Week 44 and 48. In the LN cohort, 1 patient experienced complete renal response; the remaining patients achieved stabilization/improvement in eGFR and proteinuria. All patients remain off SLE therapies (table 1B).Rese-cel peak expansion was observed within 2 weeks post infusion and B cells were reduced by 1-month post-infusion in evaluable patients. Transitional naive B cells (CD19+CD20+CD24++CD38++) began to repopulate 1-3 months post-infusion.Abstract PO:11:274 Table 1–2Conclusions These initial data suggest that rese-cel has a favorable safety profile and has the potential to reset the immune system in SLE/LN, allowing patients to achieve meaningful clinical responses off SLE therapies. Both cohorts are fully enrolled, with additional post-treatment data forthcoming.