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

Summary

study evaluates a biomarker-guided strategy to assign adults with refractory SLE to autologous CAR-T therapy targeting either CD19 or BCMA. Participants undergo centralized screening immunophenotyping to determine whether their disease appears B-cell-dominant (CD19-preferred) or plasma-cell-dominant (BCMA-preferred), followed by leukapheresis, lymphodepletion, and a single CAR-T infusion. The main goals are to assess safety, determine a recommended Phase 2 dose within each arm, and estimate remission rates by Week 24.

Eligibility

Inclusion Criteria:

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

  3\. 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.

  4\. 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%.

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

  10\. 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.

  2\. 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.

  8\. 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.

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

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

Conditions3

Interventions2

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