A Clinical Study of the Safety, Tolerability and Preliminary Efficacy of CD19/BCMA-targeted CAR-T Therapy in Refractory Autoimmune Diseases

A Clinical Study of the Safety, Tolerability and Preliminary Efficacy of CD19/BCMA-targeted CAR-T Therapy in Refractory Autoimmune Diseases

This study is an investigator-initiated single center, single arm clinical study with a target population of patients with refractory autoimmune diseases. It is an early exploratory clinical study of the safety, tolerability and initial efficacy of CD19/BCMA CAR-T in the treatment of refractory autoimmune diseases.

This open-label, single-arm clinical trial aims to evaluate the efficacy and safety of in vivo CAR-T cell therapy in patients with refractory autoimmune diseases.

No lymphodepletion conditioning regimen will be administered in this study. The lentiviral vector drug of CD19/BCMA-targeted CAR-T therapy will be infused directly.

Following infusion, subjects will undergo safety and efficacy assessments for up to 24 months to determine whether disease control is achieved.

Inclusion Criteria:

1. Age: 18~70 years old, male or female; provided written informed consent form (ICF).

2. Diagnosis of one of the following diseases:

   1. Systemic lupus erythematosus (SLE), diagnosed according to the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 criteria, with Antinuclear Antibody (ANA) > 1:80 or positive anti-dsDNA antibody;
   2. Sjögren's syndrome (SS), diagnosed according to the 2016 ACR/EULAR criteria, with at least positive anti-Sjögren's-syndrome-related antigen A antibody (SSA) antibody;
   3. Systemic sclerosis (SSc), diagnosed according to the 2013 ACR/EULAR criteria, with ANA > 1:80 or positive anti-Scleroderma (SCL)-70 antibody;
   4. Dermatomyositis (DM), meeting the 1975 Bohan and Peter criteria for DM or the 2020 European Neuromuscular Centre (ENMC)-DM classification criteria;
   5. Antisynthetase syndrome (ASS), meeting the 2010 Conners classification criteria or the 2011 Solomon classification criteria;
   6. Immune-mediated necrotizing myopathy (IMNM), meeting the 2020 ACR/EULAR classification criteria;
   7. Rheumatoid arthritis (RA), meeting the ACR/EULAR classification criteria for RA;(8) Antineutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or eosinophilic granulomatosis with polyangiitis (EGPA), diagnosed according to the 2022 ACR/EULAR criteria, with positive ANCA (any of c-ANCA, p-ANCA, anti-Proteinase 3 (PR3), or anti-Myeloperoxidase (MPO) positive).

3. Patients who have received treatment with ≥ 2 immunosuppressants for 3 months,or require prednisone ≥ 15 mg daily to maintain stable disease,or are intolerant to standard therapy, or have relative contraindications to standard therapy,and meet the following disease activity criteria:

   1. For SLE patients: SLEDAI score ≥ 8;
   2. For SS patients: EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score ≥ 14;
   3. For SSc patients: modified Rodnan Skin Score (mRSS) score 10-35 (inclusive), and/or complicated with interstitial lung disease (ILD);
   4. For DM patients: disease duration ≥ 1 year, and meeting all of the following:a. Skin rash Visual Analogue Scale (VAS) score (based on MDAAT) ≥ 3 cm, with at least 3 abnormal Cutaneous, Skeletal Muscle, Systemic (CSM) items;b. Active inflammation demonstrated by muscle biopsy, muscle MRI, or muscle ultrasound;c. Elevation of at least one muscle enzyme [creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST)] to a minimum level of 1.3 × upper limit of normal (ULN);
   5. For ANCA-AAV patients: Birmingham Vasculitis Activity Score (BVAS) ≥ 15, with positive ANCA.

4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

5. Organ function meeting the following criteria:

   1. Hematology: hemoglobin ≥ 60 g/L, platelet count ≥ 20 × 10⁹/L;
   2. Cardiac function: left ventricular ejection fraction (LVEF) ≥ 55%, no significant abnormality on electrocardiogram;
   3. Renal function: estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73 m²;
   4. Hepatic function: AST and ALT ≤ 3.0 × ULN, total bilirubin ≤ 2.0 × ULN;
   5. Eligible for leukapheresis or venous blood collection, with no other contraindications to cell collection.

6. Female subjects of childbearing potential must have a negative urine pregnancy test and agree to use effective contraception during the study until 1 year after infusion.

7. The patient or legal guardian agrees to participate in this clinical study, signs the informed consent form, and demonstrates understanding of the purpose and procedures of the study.

Exclusion Criteria:

1. Prior treatment with CAR-T cell therapy;
2. Suffering from severe cardiac, hepatic, pulmonary, hematological, or endocrine diseases, for whom the investigator determines that the risks of participation outweigh the benefits;
3. Active infection requiring systemic therapy or uncontrolled infection within 1 week prior to screening;
4. Prior hematopoietic stem cell transplantation or solid organ transplantation (excluding corneal and hair transplantation), or acute graft-versus-host disease (GVHD) of Grade 2 or higher within 2 weeks prior to screening;
5. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood hepatitis B virus (HBV) DNA titer above the normal reference range;or positive for hepatitis C virus (HCV) antibody with peripheral blood HCV RNA titer above the normal reference range;or positive for human immunodeficiency virus (HIV) antibody;or positive for syphilis;or positive for cytomegalovirus (CMV) DNA;
6. Administration of live vaccines within 4 weeks prior to screening;
7. Positive pregnancy test;
8. Patients with malignant tumors or other malignant diseases prior to screening, excluding adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, localized prostate cancer after radical treatment, and ductal carcinoma in situ after radical surgery;
9. Patients who participated in other clinical trials within 3 months prior to screening;
10. Any other conditions deemed by the investigator to render the subject ineligible for this study.