RESET SLE: CLINICAL TRIAL EVALUATING CABA-201, A FULLY HUMAN, AUTOLOGOUS 4-1BB ANTI-CD19 CAR T CELL THERAPY IN NONRENAL SLE AND LUPUS NEPHRITIS

O029 / #396 Topic: AS24 - SLE-Treatment ABSTRACT CONCURRENT SESSION 04: ADVANCING LUPUS THERAPIES AND INSIGHTS 22-05-2025 1:40 PM - 2:40 PM Background/Purpose The goal of current therapies for systemic lupus erythematosus (SLE) is to control disease activity, reduce organ damage, and decrease long-term morbidity and mortality. Therapies providing durable clinical responses without requiring chronic immunosuppressive drugs are lacking. CD19-targeting chimeric antigen receptor (CAR) T cells have achieved durable drug-free responses in SLE participants in an academic program. CABA-201 is a fully human, autologous 4-1BB anti-CD19-CAR T cell therapy, designed to deeply and transiently deplete CD19 positive cells following a one-time infusion. This approach may enable an “immune system reset” with the potential for durable response without chronic immunosuppression. RESET-SLE TM ( NCT06121297 ) is an ongoing Phase 1/2 trial evaluating safety and efficacy of CABA-201 in 2 independent SLE cohorts of nonrenal SLE and lupus nephritis (LN). Methods Eligible participants are ≥18 to ≤65 years with SLE, ANA+ or anti-dsDNA+, and SLEDAI 2K ≥8 despite standard of care (SOC) therapy (nonrenal cohort) or active, biopsy-confirmed class III or IV ± V LN despite SOC (LN cohort). A single infusion of 1x10 6 CAR T cells/kg is administered following a preconditioning regimen (fludarabine 25 mg/m 2 /d on Days -5, -4 and -3, and cyclophosphamide1,000 mg/m 2 on Day -3). All noncorticosteroid immunosuppressive and antimalarial agents are stopped by preconditioning. Participants require a minimum of 4 days in participant monitoring post-CABA-201 infusion. The primary endpoint is safety and tolerability within 28 days of infusion. Secondary endpoints include translational assessments (including CAR T cell pharmacokinetics and impact on peripheral B cell populations) and efficacy outcomes (including SLEDAI-2K, SRI and renal responses). Results As of 23 October 2024, 4 participants have been dosed with CABA-201 in the RESET-SLE TM trial, 3 participants in the nonrenal SLE cohort and 1 participant with class III nephritis in the LN cohort (Table 1). CABA-201 has been well tolerated with Grade 1 cytokine release syndrome (CRS) (fever) reported in 2 participants. The LN participant also experienced Grade 4 immune effector cell-associated neurotoxicity syndrome (ICANS), which resolved rapidly and completely following standard management. This participant had recent fevers and very active, refractory disease (SLEDAI-2K =22 at baseline despite being on 5 systemic treatments for SLE), including hospitalization for pericardial effusion 18 days prior to infusion and aseptic fever 4 days prior to infusion. Subsequently, the protocol was revised to include a delay of at least 2 weeks from any febrile event or infection prior to CABA-201 infusion and the use of antiseizure prophylaxis (as reported in previous academic data) in all participants. Early clinical response has been observed in all 4 treated participants. Each participant remains off all SLE-related immunosuppression with 2 completing a steroid taper. Translational data from 3 of the first 4 participants show that expansion of CABA-201 peaked between day(D) 15 and D29 post infusion, with the LN participant also having a 2nd peak at D29, followed by rapid contraction. Peripheral B cells were rapidly reduced with nadir occurring D22 post infusion. B cells with a translational naïve phenotype were detected at 2 months post infusion in the first 2 participants to date. Table 1. Baseline characteristics of CABA-201 treated participants Conclusions Data from SLE participants dosed with CABA-201 show CAR T cell expansion, peripheral B-cell depletion, CRS grade and frequency and clinical response consistent with previously reported data. These initial data suggest the potential for CABA-201 to reset the immune system in SLE participants and allow participants to discontinue immunosuppressive therapies and taper corticosteroids while achieving compelling clinical responses.