Lupus Nephritis, REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS
Conditions
Keywords
autologous T cells, B-cell depletion, BCMA, biomarker-guided therapy, CAR-T, CD19, immune reset, lupus nephritis, plasma-cell depletion, refractory lupus
Brief 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.
Detailed description
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.
Interventions
BIOLOGICALAutologous anti-CD19 CAR-T cells, intravenous single infusion at protocol-defined dose level (1 x 10^6 or 3 x 10^6 CAR-positive viable T cells/kg).
Autologous anti-CD19 CAR-T cells are patient-derived T lymphocytes that are genetically engineered to target CD19-expressing B cells. In clinical trials, a single intravenous infusion is administered at a protocol-defined dose (e.g., 1 × 10⁶ or 3 × 10⁶ CAR-positive viable T cells per kg) to evaluate safety, tolerability, and preliminary efficacy.
DRUGFludarabine
30 mg/m2/day IV on Days -5 to -3.
DRUGCyclophosphamide
300 mg/m2/day IV on Days -5 to -3.
Sponsors
Beijing Biotech
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-label conduct is required because the assigned CAR-T product is individualized, target selection is biomarker-driven, and early toxicity management requires full knowledge of the product received.
Intervention model description
Two experimental arms run in parallel. A pre-specified target-selection algorithm assigns each participant to the CD19 arm or BCMA arm after screening based on flow-cytometry target expression, serologic activity, prior response to B-cell-depleting therapy, and renal/plasma-cell biomarkers where relevant. Each arm includes a dose-finding safety lead-in followed by cohort expansion at the selected dose.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting toxicities (DLTs) | 28 days | Incidence of protocol-defined DLTs, including product-related Grade 3 or higher non-hematologic toxicity and prolonged severe cytopenia. |
| Incidence and severity of cytokine release syndrome (CRS) | 28 | Incidence and severity of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, graded by ASTCT criteria. |
| Protocol-defined lupus response | 24 weeks | Proportion of participants achieving DORIS remission without rescue therapy or, for those with active baseline LN, complete renal response without rescue therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete renal response in LN subgroup | 52 weeks | Renal response rate in participants with active lupus nephritis at baseline. |
Countries
China
Contacts
CONTACTshan S Lu, Phd
Outcome results
None listed