SELECT-SLE: Biomarker-Guided CAR-T Target Selection for Refractory Lupus

SLE is frequently sustained by autoreactive CD19-positive B cells, plasmablasts, and long-lived plasma cells. CD19-directed CAR-T can produce profound B-cell depletion and immune reset, whereas BCMA-directed CAR-T may better address plasma-cell-dominant disease, especially persistent autoantibody production or lupus nephritis after prior B-cell-depleting therapy. This example trial prospectively assigns participants to the target most likely to match their dominant pathogenic compartment. At screening, a central review committee evaluates flow cytometry target expression, serum autoantibody burden, complement levels, immunoglobulins, prior response to rituximab or similar agents, and renal/plasma-cell biomarkers where relevant. Each arm includes a safety lead-in with dose escalation followed by an expansion cohort at the recommended Phase 2 dose. All participants undergo leukapheresis, optional protocol-limited bridging therapy, fludarabine/cyclophosphamide lymphodepletion, single CAR-T infusion, inpatient monitoring, and follow-up through 52 weeks, plus separate long-term gene-modified-cell safety surveillance.

Inclusion criteria

• 1. Age 18 to 70 years at consent. 2. Meets 2019 EULAR/ACR classification criteria for SLE, with total score >= 10.

• Active refractory disease at screening, defined by SELENA-SLEDAI >= 8, or at least one BILAG A domain, or at least two BILAG B domains, or active lupus nephritis with significant proteinuria and active urinary sediment.

• Inadequate response, intolerance, or contraindication to at least 2 prior standard systemic regimens, including at least 1 immunosuppressant or biologic used for SLE or lupus nephritis. 5. Demonstrable targetable biology and assignment to one protocol arm: CD19 arm for measurable CD19-positive B-cell / B-cell-dominant disease, or BCMA arm for BCMA-positive plasmablast / plasma-cell-dominant disease and/or persistent serologic activity after prior B-cell depletion. 6. If active lupus nephritis is present, biopsy-proven class III, IV, V, or mixed proliferative / membranous LN within the previous 24 months, or investigator confirmation that repeat biopsy is unsafe but the clinical picture strongly supports active LN. 7. Adequate organ function: hemoglobin >= 8.5 g/dL, ANC >= 1.0 x 10^9/L, platelets >= 50 x 10^9/L, AST / ALT <= 2.5 x ULN, creatinine clearance >= 30 mL/min, bilirubin <= 2.0 mg/dL unless otherwise explained, and LVEF >= 50%.

• Adequate venous access and eligibility for leukapheresis. 9. Negative pregnancy test and agreement to use effective contraception for 12 months after infusion.

• Ability to discontinue prohibited SLE medications per washout rules and willingness to comply with inpatient observation and long-term follow-up. 11. Written informed consent.

Exclusion criteria

• 1. Active uncontrolled infection, including active tuberculosis, hepatitis B or C with active replication, or HIV.

• Prior CAR-T therapy or prior CD19- or BCMA-directed cell therapy. 3. Severe active CNS lupus requiring urgent escalation of immunosuppression, uncontrolled seizure disorder, or stroke within 60 days before screening. 4. End-stage organ failure not expected to improve with immune reset, such as dialysis-dependent kidney failure, uncontrolled advanced heart failure, or ICU-level respiratory instability. 5. Active malignancy or history of malignancy within 5 years, except adequately treated non-melanoma skin cancer, cervical carcinoma in situ, or other low-risk malignancy in durable remission. 6. Pregnant or breastfeeding. 7. Allogeneic hematopoietic stem cell transplant or solid organ transplant history.

• Contraindication to fludarabine, cyclophosphamide, leukapheresis, or standard rescue medications for CRS / ICANS. 9. Live vaccine within 4 weeks before lymphodepletion. 10. Participation in another interventional clinical study within 3 months before enrollment.

• Uncontrolled psychiatric disease, active substance misuse, or social circumstances that would impair adherence.

• Any condition that, in the investigator's judgment, makes participation unsafe or confounds interpretation of the study endpoints.