Study of Ultra-Fast BCMA/CD70 CAR-T Therapy for Refractory SLE

Official title

Study of Ultra-Fast Autologous BCMA/CD70-Targeted Chimeric Antigen Receptor T (CAR- T) Therapy for Refractory Systemic Lupus Erythematosus

Overview

This is an investigator-initiated trial aimed at assessing the safety and efficacy of ultra-fast autologous BCMA/CD70-targeted CAR-T cells in the treatment of refractory systemic lupus erythematosus.

Detailed description

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 disease-related antigens through antigen-specific recognition. Since 2019, CAR-T cell therapy has been successfully applied to autoimmune diseases. Clinical studies have demonstrated that 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 BCMA/CD70-targeted CAR-T cells in the treatment of refractory SLE.

Interventions

• Biological BCMA/CD70 CAR-T cells
  Three dose groups (1.5×10\^5/kg, 5×10\^5/kg, 10×10\^5/kg) were set up, starting from the low dose group climbing to explore the safe and effective dose.

Primary outcome measures

• The safety of CAR-T cell therapy in patients with refractory SLE [Safety] [Time frame: 3 months]
• The changes from baseline in SLEDAI-2K [efficacy] [Time frame: 6 months]
• The changes from baseline in PGA [efficacy] [Time frame: 6 months]
• The changes from baseline in BILAG-2004 [efficacy] [Time frame: 6 months]
• The number of patients with SRI-4 response [efficacy] [Time frame: 3 months]
• The number of patients with LLDAS [efficacy] [Time frame: 6 months]
• The number of patients with DORIS [efficacy] [Time frame: 6 months]

Secondary outcome measures (10)

• The changes of anti-ds-DNA antibody after infusion [efficacy] [Time frame: 6 months]
• The changes of 24h urine protein after infusion [efficacy] [Time frame: 6 months]
• The changes of serum complement C3 and C4 after infusion [efficacy] [Time frame: 6 months]
• Cmax of CAR-T cells [PK parameter] [Time frame: 3 months]
• Tmax of CAR-T cells [PK parameter] [Time frame: 3 months]
• AUC28d/90d of CAR-T cells [PK parameter] [Time frame: 3 months]
• The degree of B cell and T cell depletion [PD parameter] [Time frame: 3 months]
• The concentration levels of IL-6 [PD parameter] [Time frame: 3 months]
• The concentration levels of CRP [PD parameter] [Time frame: 3 months]
• The concentration levels of ferritin [PD parameter] [Time frame: 3 months]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years old;
• 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), and/or 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;
• 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 until one year after CAR-T infusion;
• Participant or his/her guardians agree 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.

Exclusion criteria

• Central nervous system (CNS) disease: CNS neurolupus requires intervention within 30 days;
• Have a history of congenital heart disease or acute myocardial infarction within 6 months prior to screening or severe arrhythmias (including multisource frequent supraventricular tachycardia, ventricular tachycardia, etc.); or NYHA classification class IV; or combined with moderate to massive pericardial effusion, serious myocarditis, etc; or patient with unstable vital signs who need hypertensive drugs;
• The functions of important organs meet one of the following conditions: (1)renal function: eGFR<30mL/min/1.73m2 or require renal replacement therapy; (2)liver function: AST and ALT>3.0 ULN, total Bilirubin (TBIL) in serum >2.0×ULN; (3)lung function: SpO2<92% with no oxygen inhalation;
• Uncontrollable infection or active infection that requires systemic treatment within 3 months prior to screening;
• Received 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 active pulmonary tuberculosis at screening;
• Received live vaccine within 4 weeks prior to screening;
• Positive in blood pregnancy test;
• Suffered from malignant disease such as tumors (excluding tumors without active lesions and ending treatment for more than 5 years, as well as fully treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, thyroid cancer after radical resection, ductal carcinoma in situ after radical resection);
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Affiliated Drum Tower Hospital, Medical School of Nanjing University — Nanjing

Identifiers

NCT: NCT07318259 · PBC093

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗