Study of Ultra-Fast Autologous CD19-targeted Chimeric Antigen Receptor T (CAR- T) Therapy for Refractory Systemic Lupus Erythematosus
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- The changes from baseline in PGA [efficacy]
研究概览
简要总结
This is an investigator-initiated trial aimed at assessing the safety and efficacy of ultra-fast autologous CD19-targeted CAR-T cells in the treatment of refractory systemic lupus erythematosus.
详细描述
Systemic lupus erythematosus (SLE) is a serious autoimmune disease that can lead to extensive damage in multiple organs and systems, ultimately resulting in disability and even death.
Currently, the primary treatment for SLE relies on glucocorticoids and immunosuppressants to alleviate symptoms. However, due to the absence of a curative treatment, patients typically need to remain on medication indefinitely. In recent years, biological agents such as belimumab and rituximab have been introduced for the treatment of SLE, but these treatments cannot completely eliminate autoimmune B cells in the bone marrow, leading to unsatisfactory overall outcomes. Furthermore, discontinuing these drugs can lead to disease relapse, and there is still no cure for SLE, leaving patients facing the challenges of lifelong medication and an incurable disease.
CAR-T therapy is an adoptive cell therapy that uses genetic modification technology to reprogram T cells and eliminate target cells expressing diseaserelated antigens through antigen-specific recognition. Since 2019, CAR-T cell therapy has been successfully applied to autoimmune diseases. Clinical studies have demonstrated that CD19-targeted CAR-T cells hold significant therapeutic potential for SLE. Compared with traditional CAR-T cells, ultra-fast CAR-T, relying on an innovative CAR-T manufacturing system, can produce CAR-T cells in an extremely short period of time (with a preparation time of only 10 minutes).
The purpose of this study is to assess the safety and efficacy of the ultra-fast autologous CD19-targeted CAR-T cells in the treatment of refractory SLE.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 5 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: ≥ 5 years old, and no gender limitation;
- •Diagnosed with SLE according to the 2019 EULAR/ACR SLE classification criteria, and still in moderate to severe disease activity despite ≥3M of high dose glucocorticoids(prednisone≥1mg/kg/d or other equivalent amount of other steriod), hydroxychloroquine and at least 2 DMARDs(include cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate, cyclosporin, tacrolimus, sirolimus, leflunomide, telitacicept, Beliumab, and rituximab) or intolerant to standard treatments;
- •SLEDAI-2K score≥8 points;
- •The functions of important organs are basically normal:
- •Cardiac function: Left ventricular ejection fraction (LVEF) ≥55% with no obvious abnormality in electrocardiogram;
- •Renal function: eGFR≥30mL/min/1.73m2;
- •Liver function: AST and ALT≤3.0 ULN, total Bilirubin (TBIL) in serum ≤2.0×ULN;
- •Lung function: no serious lung lesions, SpO2≥92%;
- •Meet the standards of leukapheresis or intravenous blood collection, and no contraindication for leukapheresis;
- •Negative pregnancy test for female subjects of childbearing age, and agree to take effective contraceptive measures the first year after CAR-T infusion;
- •Participants or their guardians agrees to participate in the clinical trial and sign the informed consent form which indicating that he/she understands the purpose and procedure of the clinical trial and is willing to participate in the study.
排除标准
- •Central nervous system (CNS) disease: CNS neurolupus requires intervention within 60 days);
- •Severe acute nephritis: patients who have accepted or was undergoing renal replacement therapy within 3 months prior to transfusion; or in the investgator's opinion, patients who is likely to have significant kidney disease within 3 moths of the study which need high dose glucocorticoid (prednisone dose≥1mg/kg/day or equivalent amount of other steriod), cyclophosphamide, or mycophenolate mofetil treatment;
- •Have a history of congenital heart disease or severe arrhythmias (including multisource frequent supraventricular tachycardia, ventricular tachycardia, etc.); or combined with moderate to massive pericardial effusion, serious myocarditis, etc; or patients with unstable vital signs who need hypertensive drugs;
- •Uncontrollable infection, or active infection that requires systemic treatment within 3 months prior to screening;
- •Received organ transplantation or hematopoietic stem cell transplantation within 3 months prior to screening, or ≥Grade 2 GVHD within 2 weeks prior to screening;
- •Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer greater than the normal reference value range; or hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C virus (HCV) RNA titer greater than the normal reference value range; or positive for human immunodeficiency virus (HIV) antibodies; or syphilis test positive;
- •Suffered from macrophage activation syndrome(MAS) within 1 month prior to screening (except for those whose safety risks have been ruled out by the researcher after treatment);
- •Received CAR-T treatment (except for those whose safety risks have been ruled out by the researchers after treatment);
- •Suffered from active pulmonary tuberculosis at screening;
- •Received live vaccine within 4 weeks prior to screening;
- •Positive in Blood pregnancy test;
- •Previous or concurrent malignancy;
- •Patients who participated in other clinical study within 3 months prior to screening;
- •Any other conditions that the investigators deem it unsuitable for the study.
研究组 & 干预措施
CAR-T treatment group
This trial was designed as an open, single-arm, single-center, dose-increasing trial.
干预措施: CD19 CAR-T cells (Biological)
结局指标
主要结局
The changes from baseline in PGA [efficacy]
时间窗: 6 months
Physician Global Assessment(PGA) is a continuous visual analogue scale with 0, 1, 2, and 3 scales. "0" indicates no disease activity and "3" indicates the most severe disease activity.
The safety of CAR-T cell therapy in patients with refractory SLE [Safety]
时间窗: 3 months
Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs and other clinical manifestation assessed by CommonTerminology Criteria for Adverse Events (CTCAE) v5.0.
The changes from baseline in SLEDAI-2K [efficacy]
时间窗: 6 months
Systemic Lupus Erythematosus Disease Activity Index 2000(SLEDAI-2K) is from 0 to 105 points. The higher score means the stronger disease activity.
The changes from baseline in BILAG-2004 [efficacy]
时间窗: 6 months
British Isles Lupus Assessment Group Index 2004(BILAG-2004) consists of 8 systems, each of which is classified as A, B, C and D respectively. "A" indicates that the condition is highly active and requires active treatment. "B" indicates that the condition is active and requires close monitoring or symptomatic treatment. "C" indicates a stable condition. "D" indicates that the system is not involved.
The number of patients with SRI-4 response [efficacy]
时间窗: 3 months
The definition of SRI-4 response: SLEDAI-2K ≥ 4-Point improvement; PGA with no worsening (\<0.3-point increase); BILAG 2004 with no new A domain score and no more than 1 new B domain scores.
The number of patients with LLDAS [efficacy]
时间窗: 6 months
The definition of LLDAS: SLEDAI-2K ≤ 4 and no disease activity in major organs (kidneys, central nervous system, heart and lungs), and no vasculitis or fever; no new disease activity symptoms were added compared with previous disease assessments; PGA ≤ 1; irrespective of serology; with permitted use of low-dose glucocorticoids (prednisolone ≤ 7.5 mg/day), and/or stable immunosuppressives and biologics.
The number of patients with DORIS [efficacy]
时间窗: 6 months
The definition of DORIS: SLEDAI-2K = 0 ; PGA) \< 0.5 ; irrespective of serology; with permitted use of antimalarials, low-dose glucocorticoids (prednisolone ≤ 5 mg/day), and/or stable immunosuppressives and biologics.
次要结局
- The changes of anti-ds-DNA antibody after infusion [efficacy](6 months)
- Cmax of CAR-T cells [PK parameter](3 months)
- Tmax of CAR-T cells [PK parameter](3 months)
- The changes of C3 and C4 after infusion [efficacy](6 months)
- The number of remission of lupus nephritis [efficacy](6 months)
- The changes of 24h urine protein after infusion [efficacy](6 months)
- AUC28d/90d of CAR-T cells [PK parameter](3 months)
- The degree of B cell depletion [PD parameter](3 months)
- The concentration levels of IL-6 [PD parameter](3 months)
- The concentration levels of CRP [PD parameter](3 months)
- The concentration levels of ferritin [PD parameter](3 months)
研究者
Mao Jianhua
Principal investigator
The Children's Hospital of Zhejiang University School of Medicine