2458: Obecabtagene autoleucel (obe-cel), a CD19-targeting Autologous Chimeric Antigen Receptor T-cell Therapy (CAR T) with a fast off-rate binding domain, in Patients (pts) with Severe, Refractory Systemic Lupus Erythematosus (srSLE): Preliminary Results from the Phase I CARLYSLE Study

Background/Purpose: Pts with srSLE have limited remaining treatment options and represent a population with an unmet need. CD19 CAR Ts have potential for deep depletion of the B-cell lineage, including plasmablasts. Obe-cel is an autologous CD19-directed CAR T with a fast off-rate binding domain designed to reduce immunotoxicity, approved in adult relapsed/refractory B-cell acute lymphoblastic leukemia. We report initial safety and preliminary efficacy results from the single-arm, open-label, dose-finding, Phase I CARLYSLE study (NCT06333483).

Methods: Eligible pts (12–65 years old) had a diagnosis of SLE based on the 2019 EULAR/ACR criteria and a ≥8-point SLEDAI-2K score at screening with ≥1 major SLE-related organ involvement, and were refractory to multiple prior standard-of-care SLE medications. Immunosuppressants were tapered off prior to apheresis. Following lymphodepletion with fludarabine (3×25 mg/m²) and cyclophosphamide (1x1,000 mg/m²), obe-cel was administered as a single starting target dose of 50×10⁶ (±20%) CAR T-cells. Primary endpoints: incidence of dose limiting toxicities (DLTs) within 28 days of infusion; frequency of adverse events. Secondary endpoints included: SLEDAI-2K; PGA; pharmacokinetics (PK); autoantibody and biomarker levels over time.

Results: As of 17 Mar 2025, seven pts had been enrolled and six had been infused with obe-cel with up to 8 months of follow up. At baseline, all infused pts had severe, refractory, active SLE (SLEDAI-2K score range: 15–28). All infused pts had class III or IV lupus nephritis; four also had class V. Four pts had elevated serum creatinine and an estimated glomerular filtration rate of < 60 mL/min/1.73m²; six pts had elevated urinary protein-creatinine ratio. Pts were refractory to B-cell targeting agents and immunosuppressants (median: 5 prior medicines; range: 5–6). No DLTs or immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Three pts experienced Grade (Gr) 1 cytokine release syndrome (CRS) with no Gr ≥2 CRS. Transient hypertension was observed in five pts. All pts had Gr ≥3 neutropenia. Infections were transient and manageable; no life-threatening infections were observed. A ≥10 point reduction in SLEDAI-2K scores was seen in the four pts who had ≥3 months of follow up and all non-renal manifestations completely resolved within 3 months. Steroid doses were tapered to ≤10mg/day post obe-cel infusion; no other SLE medications were administered. Three of six pts had a complete renal response (CRR) at last follow-up, one at Month 1 (M1) and two at M3. Complement C3 normalized and anti-double-stranded DNA antibody decreased in all six pts by M1 compared with baseline levels. PK data indicated robust CAR T-cell expansion; peak expansion was reached at a median of 10 days. Three pts had ongoing CAR T-cell persistence at last follow-up.

Conclusion: Initial findings from the ongoing CARLYSLE study of obe-cel in srSLE show a manageable safety profile, with no DLTs, ICANS or Gr ≥2 CRS. SLEDAI-2K score reduction and clinical benefit were observed in all pts, including three pts who had a CRR. Despite the short follow up and small number of pts, initial findings are promising; further research is warranted. Updated data will be presented at the conference.