A Phase 1/2, Open-Label, Biomarker-Guided, Non-Randomized, Multicenter Study of Autologous CAR-T Cell Therapy Targeting CD19 or BCMA in Adults With Refractory Systemic Lupus Erythematosus With or Without Active Lupus Nephritis.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Dose-limiting toxicities (DLTs)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Age 18 to 70 years at consent.
- •Meets 2019 EULAR/ACR classification criteria for SLE, with total score >=
- •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.
- •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.
- •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.
- •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.
- •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.
- •Written informed consent.
排除标准
- •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.
- •Severe active CNS lupus requiring urgent escalation of immunosuppression, uncontrolled seizure disorder, or stroke within 60 days before screening.
- •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.
- •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.
- •Pregnant or breastfeeding.
- •Allogeneic hematopoietic stem cell transplant or solid organ transplant history.
- •8. Contraindication to fludarabine, cyclophosphamide, leukapheresis, or standard rescue medications for CRS / ICANS.
- •Live vaccine within 4 weeks before lymphodepletion.
- •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.
研究组 & 干预措施
CD19-selected
Participants with a B-cell-dominant disease profile (for example, measurable circulating CD19-positive B cells, active serology, and no strong evidence of plasma-cell-dominant refractory disease) receive autologous anti-CD19 CAR-T cells after lymphodepletion.
干预措施: Autologous 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). (Biological)
BCMA-Selected CAR-T
Participants with a plasma-cell-dominant or BCMA-preferred profile (for example, persistent autoantibody production after prior B-cell depletion, high plasmablast/plasma-cell markers, or active nephritis with ongoing serologic activity) receive autologous anti-BCMA CAR-T cells after lymphodepletion.
干预措施: Autologous 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). (Biological)
BCMA-Selected CAR-T
Participants with a plasma-cell-dominant or BCMA-preferred profile (for example, persistent autoantibody production after prior B-cell depletion, high plasmablast/plasma-cell markers, or active nephritis with ongoing serologic activity) receive autologous anti-BCMA CAR-T cells after lymphodepletion.
干预措施: Fludarabine (Drug)
CD19-selected
Participants with a B-cell-dominant disease profile (for example, measurable circulating CD19-positive B cells, active serology, and no strong evidence of plasma-cell-dominant refractory disease) receive autologous anti-CD19 CAR-T cells after lymphodepletion.
干预措施: Fludarabine (Drug)
BCMA-Selected CAR-T
Participants with a plasma-cell-dominant or BCMA-preferred profile (for example, persistent autoantibody production after prior B-cell depletion, high plasmablast/plasma-cell markers, or active nephritis with ongoing serologic activity) receive autologous anti-BCMA CAR-T cells after lymphodepletion.
干预措施: Cyclophosphamide (Drug)
CD19-selected
Participants with a B-cell-dominant disease profile (for example, measurable circulating CD19-positive B cells, active serology, and no strong evidence of plasma-cell-dominant refractory disease) receive autologous anti-CD19 CAR-T cells after lymphodepletion.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Dose-limiting toxicities (DLTs)
时间窗: 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)
时间窗: 28
Incidence and severity of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, graded by ASTCT criteria.
Protocol-defined lupus response
时间窗: 24 weeks
Proportion of participants achieving DORIS remission without rescue therapy or, for those with active baseline LN, complete renal response without rescue therapy.
次要结局
- Complete renal response in LN subgroup(52 weeks)