Obecabtagene autoleucel (obe-cel), a CD19-targeting chimeric antigen receptor (CAR) T-cell therapy, in patients with severe, refractory systemic lupus erythematosus (SLE) in the Phase I CARLYSLE study: Initial safety, preliminary efficacy, pharmacoki

Abstract Background: CAR T-cell therapy has shown promising early results in patients (pts) with SLE through deep depletion of the B-cell lineage, including plasmablasts. Obe-cel is an autologous 4-1BB-ζ CD19-directed CAR T-cell therapy with a fast off-rate binding domain and demonstrated clinical efficacy in adult relapsed/refractory B-cell acute lymphoblastic leukemia (Roddie et al. NEJM 2024). We report initial safety, preliminary efficacy, pharmacokinetics (PK), and biomarker analyses in pts with severe, refractory SLE, treated with obe-cel in the ongoing Phase I CARLYSLE study (NCT06333483). Methods: CARLYSLE is a single-arm, open-label, dose-finding study, in pts aged 12–65 years with severe, refractory SLE, who are predicted to have a poor outcome with standard therapy and for whom clinical trials may be a potential option to improve their prognosis. Eligible pts had an SLE diagnosis per the 2019 EULAR/ACR criteria, ≥8-point SLE Disease Activity Index 2000 (SLEDAI-2K) score at screening with ≥1 major SLE-related organ involvement and were refractory to multiple standard therapies. Immunosuppressants were tapered prior to apheresis. Following bridging therapy with steroids as needed and lymphodepletion (LD; fludarabine [25 mg/m2×3], cyclophosphamide [1000 mg/m2]), obe-cel was administered to the first six pts as a single flat dose of 50×106 (±20%) CAR T-cells. An escalated dose of 100×106 CAR T-cells was then administered to additional pts. Only a maintenance dose of ≤10 mg/day prednisone/equivalent was permitted post infusion. Primary endpoints: incidence of dose-limiting toxicities (DLTs) within 28 days of infusion, and frequency of adverse events. Secondary endpoints: disease response (SLEDAI-2K and Physician's Global Assessment [PGA] scores), biomarker analyses, PK, and pharmacodynamics. Results: As of 9 July 2025, 10 pts were enrolled in CARLYSLE. We report data on the first 6 obe-cel infused pts (data cut: 17 March 2025; follow-up range: 1–8 months [mos], ≥3 mos in 4 pts; ≥1 mo in 2 pts). At baseline, all 6 infused pts (age range: 19–50 years) had severe, refractory active SLE (SLEDAI-2K score range: 15–28), class III or IV lupus nephritis (4 pts also had class V), with elevated urinary protein-creatinine ratio (UPCR; n=6; median: 2.17 mg/mg [range: 0.49–4.02]) and serum creatinine (n=4; median: 128 µmol/L [range: 123–222]). All pts had inadequate response to a median of 5 prior immunosuppressive treatments, including B-cell targeting agents and calcineurin inhibitors. No DLTs, immune effector cell-associated neurotoxicity syndrome, or Grade ≥2 cytokine release syndrome (CRS) events were seen; 3 pts experienced Grade 1 CRS. Most treatment-emergent adverse events were low grade (≤2). Transient Grade 3 or 4 neutropenia (n=6), and transient or manageable hypertension (n=5; pre-existing medical condition in n=3) were observed after LD and obe-cel infusion. No pts experienced disease flares and no rescue SLE medications were administered. The 4 pts with ≥3 mos follow-up experienced rapid clinical improvements with a ≥10-point reduction in SLEDAI-2K scores (range: 10–26 point reductions from Month [M] 3) and a clinically meaningful reduction (to ≤1) in PGA scores. Three of 6 pts achieved a complete renal response by M3 with resolution of proteinuria (achieved UPCR ≤0.5 mg/mg). Complement C3 normalized and anti-double-stranded DNA antibody decreased in all 6 pts by M1 compared with baseline levels. PK data indicated robust CAR T-cell expansion (median time to maximal expansion: 9.9 days), with a geometric mean of maximal expansion of 86,585 copies/μg DNA, coupled with undetectable B-cell levels as of Day 8. M1 cytokine profiling showed a transient increase in interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor alpha levels (peak observed at time of maximal CAR T-cell expansion). Three of 4 pts had B-cell recovery between M3 and M6; double-negative and memory B-cells were mostly eliminated, and reconstituted B-cells consisted primarily of naïve B-cells. Conclusions:Initial findings from the ongoing CARLYSLE study of obe-cel in severe, refractory SLE are promising and suggest a favorable safety profile with obe-cel treatment, with no DLTs, pronounced CAR T-cell expansion, and observed clinical benefit. The B-cell reconstitution profiles suggest that obe-cel may induce a reset of pathologic autoimmunity. Updated Phase I data with longer follow-up, and data in pts who received 100×106 CAR T-cells will be presented.