2468: RESET-SLE: Clinical Trial Evaluating Rese-cel (Resecabtagene Autoleucel), a Fully Human, Autologous 4-1BB CD19-CAR T Cell Therapy in Non-Renal SLE and Lupus Nephritis

Background/Purpose: Current goals of treatment for systemic lupus erythematosus (SLE) are to achieve low disease state/remission, prevent flares, minimize organ damage, and decrease long-term morbidity and mortality. Therapies providing durable clinical responses without requiring chronic administration are lacking. Rese-cel (formerly CABA-201) is a fully human, autologous 4-1BB CD19-CAR T cell therapy, designed to deeply and transiently deplete CD19 positive cells following a weight-based, single infusion. This approach may enable an “immune system reset” and durable meaningful clinical responses without chronic therapies. RESET-SLE^TM (NCT06121297) is an ongoing Phase 1/2 trial in 2 independent cohorts of non-renal SLE and lupus nephritis (LN).

Methods: Patients were 18 to 65 years with SLE, ANA+ or anti-dsDNA+, and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) ≥8 despite standard of care (SOC) therapy (non-renal SLE cohort), or active, biopsy-confirmed class III or IV ± V LN despite SOC (LN cohort). A single infusion of 1x10⁶ CAR T cells/kg was administered following preconditioning with fludarabine and cyclophosphamide. All non-glucocorticoid (GC) immunomodulatory (IM) agents were discontinued by Day -5. Adverse events, use of SLE medications, SLEDAI-2K changes, achievement of the definition of remission in SLE (DORIS), lupus low disease activity state (LLDAS), and renal responses were assessed. CAR T cells and B cells were profiled in peripheral blood samples pre- and post-infusion by digital PCR and flow cytometry, respectively. Serum cytokines were measured using the mesoscale discovery platform.

Results: As of 31 March 2025, 7 patients have been infused with rese-cel and have at least 4 weeks of follow-up (Table 1). One additional patient has been infused and is in early follow up.

Rese-cel was well-tolerated with Grade 1 cytokine release syndrome (CRS) reported in 2 patients (SLE-2 and LN-1). As previously reported, LN-1 experienced Grade 4 immune effector cell-associated neurotoxicity syndrome (ICANS), associated with a potential occult infection based on cytokine and TCR clonality profiling, which rapidly resolved following standard management.

Robust clinical improvement has been observed in all 7 patients (Table 2).

CAR T cells expanded rapidly and peaked between days 7 and 16 post-infusion, with LN-1 also having a second peak at day 28, followed by contraction. Serum IFNγ rapidly increased concurrently with or prior to rese-cel expansion. Peripheral B cells were rapidly reduced within the first 2 weeks and started reconstituting between 8 and 20 weeks in all patients to date. Reemergent B cells presented initially with a transitional naïve phenotype (CD19+CD20+CD38++CD24++).

Conclusion: Data from SLE and LN patients infused with rese-cel shows early clinical responses, including meeting the DORIS remission criteria and complete renal response, and an acceptable safety profile, in the setting of CAR T cell expansion and peripheral B-cell reduction. These initial data suggest the potential for rese-cel to reset the immune system in SLE and LN, allowing patients to achieve meaningful clinical responses off all IM agents.