In this study, CD19 CAR-T cells were administered to patients with relapsed/refractory autoimmune diseases. This study intends to use retroviral vector-based tandem CAR-T cells targeting CD19 to treat autoimmune disease. The CAR-T cells were provided by Shenzhen Cell Valley. A study published in the New England Journal of Medicine provides strong evidence for the therapeutic potential of CD19 CAR-T therapy in autoimmune diseases. The study enrolled 15 participants, including eight with severe SLE, three with idiopathic inflammatory myositis, and four with systemic sclerosis. The median follow-up was 15 months (4 to 29 months). Data from the clinical trial showed that all patients with SLE had a remission of DORIS, all patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, all patients with systemic sclerosis had a decrease in the EUSTAR activity index score, and all patients discontinued immunosuppressive therapy completely. The investigators look forward to expanding the use of CAR-T cells in relapsed/refractory autoimmune diseases through this safety and efficacy clinical study and greatly enhancing the quality of life for these patients.

This is a prospective, single-center, open, single-arm, dose-escalation clinical trial to evaluate the safety and efficacy of CAR-T cell therapy in patients with relapsed/refractory autoimmune diseases. Intravenous infusion will be used, and the trial procedure will be divided as follows:

1. Screening period (D-28 to D-6):

   After subjects voluntarily sign an informed consent form, a screening period will be conducted to determine whether subjects are eligible for the trial based on inclusion and exclusion criteria.

2. Lymphocyte depletion pretreatment (Study D-5 to Study D-3):

   Subjects will be pre-treated with Lymphocyte depletion starting 5 days prior to CAR-T cell infusion (FC regimen)

3. Rest and Observation (Study D-2 to Study D-1):

   Follow the study procedures and perform the relevant examinations during the rest and observation period.

4. Cell Infusion and Primary Study Endpoint Observation Period (Study D0 to W12 post-infusion):Subjects will undergo CAR-T cell infusion at 2-day intervals (Study Day 0) after lymphocyte depletion pretreatment, and post-infusion observations and safety assessments will be performed before, during, and after the cell infusion (day of infusion, days 4, 7, 10, 14, 21, and 28 post-infusion), respectively. Evaluation of efficacy: Subjects will be evaluated for efficacy on the 14th, 28th day, 8th and 12th week after CAR-T cell infusion.

5. Follow-up period (W12 to W52 after infusion):The follow-up period is for safety and efficacy evaluation. Safety follow-up: Subjects will be followed for 52 weeks after CAR-T cell infusion. Efficacy Evaluation: Subjects will be evaluated for efficacy at weeks 24, 36, and 52 after CAR-T cell infusion. In addition, the actual frequency of effectiveness evaluations may be increased at the discretion of the investigator.

Inclusion Criteria:

• age 18-65 years (including threshold) and gender;

• positive expression of CD19 in peripheral blood B cells as determined by flow cytometry;

• the function of vital organs meets the following requirements:

  1. Bone marrow function needs to meet the following requirements: a. White blood cell count ≥3×109/L; b. Neutrophil count ≥1×109/L (no colony-stimulating factor treatment within 2 weeks prior to the examination); c. Hemoglobin ≥60g/L;

  2. Liver function: ALT≤3×ULN (except for elevated ALT caused by inflammatory myopathy); AST≤3×ULN (except for AST elevation caused by inflammatory myopathy); TBIL≤1.5×ULN (except for Gilbert's disease).

     TBIL≤1.5×ULN (except Gilbert's syndrome, total bilirubin≤3.0×ULN);

  3. Renal function: creatinine clearance (CrCl) ≥ 30 ml/minute (Cockcroft/Gault formula, except for disease-induced decline in CrCl);

  4. Coagulation: international normalized ratio (INR) ≤ 1.5 x ULN, prothrombin time (PT) ≤ 1.5 x ULN.

  5. Cardiac function: hemodynamic stability;

• female subjects of childbearing potential and male subjects with a partner of childbearing potential are required to use medically approved contraception or be abstinent from sexual intercourse for at least 6 months during and after study treatment; female subjects of childbearing potential must have had a negative serum HCG test within 7 days prior to study enrollment and must not be breastfeeding;

• Voluntarily participate in this clinical study and sign the informed consent form, good compliance and cooperate with follow-up visits.

• Specific inclusion criteria:

• Relapsed refractory systemic lupus erythematosus.

• meets the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for SLE;

• have a Disease Activity Score SLEDAI⁃2000 ≥ 6; and have at least one British Isles Lupus Assessment Group Index (BILAG-2004) Category A (severe manifestations) or two Category B (moderate manifestations) organ scores, or both; or have a Disease Activity Score SLEDAI-2000 ≥ 8;

• Definition of relapse-refractory: failure of conventional treatment for more than 6 months or recurrence of disease activity after remission.

• Relapsing Refractory/Progressive Diffuse Systemic Sclerosis

• meets the 2013 ACR's classification criteria for systemic sclerosis consistent with a diffuse presentation

• is positive for antibodies related to systemic sclerosis;

• diffuse cutaneous sclerosis manifestations or active interstitial lung disease (HRCT suggestive of ground-glass exudates);

• definition of relapsing-refractory: failure of conventional treatment for more than 6 months or recurrence of disease activity after remission.

• Definition of Progressive: Rapid cutaneous progression (>25% increase in mRSS); or pulmonary progression (10% decrease in FVC, or >5% decrease in FVC with 15% decrease in DLCO).

• Note: It is sufficient if one of Articles 4 and 5 is fulfilled.

• Relapsed refractory/progressive inflammatory myopathy

• meets the 2017 EULAR/ACR classification criteria for inflammatory myopathies (including DM , PM, ASS, and NM);

• is positive for antibodies to myositis;

• in those with muscle involvement, an MMT-8 score of less than 142 and abnormal findings on at least two of the following five core measurements (PhGA, PtGA, or Extramuscular Disease Activity Score ≥2; Total HAQ Score ≥0.25); Myosin level 1.5 times the upper limit of the normal range); or MMT-8 ≥142 in the presence of active interstitial lung disease (HRCT suggestive of ground-glass exudates);

• Definition of relapse refractory: failure of conventional treatment for more than 6 months or recurrence of disease activity after remission.

• Definition of progressive: the presence of exacerbation of myositis or rapidly progressive interstitial pneumonia.

• Note: It is sufficient if one of Articles 4 and 5 is fulfilled.

• Relapsed Refractory/Progressive Immune Thrombocytopenia

• meets the 2019 American Society of Hematology (ASH) classification criteria for immune thrombocytopenia;

• have bone marrow morphology characterized by increased or normal megakaryocytes with impaired maturation;

• exclude other secondary thrombocytopenia

• Definition of recurrent refractory: a patient who fails to achieve a satisfactory outcome after first-line standard therapy (e.g., glucocorticoids), including a full dose and course of therapy, i.e., platelet counts that cannot be maintained at a safe level (generally considered to be platelet counts > 30 × 10⁹ /L and without overt bleeding symptoms).

• Definition of progressive: a sustained decline in platelet count over the course of the disease, or a progressive worsening of bleeding symptoms, which may be accompanied by signs such as splenomegaly, and a progressively worse response to conventional therapy.

• Note: It is sufficient if one of Articles 4 and 5 is fulfilled.

Exclusion Criteria:

• A history of severe drug allergies or sensitivities;
• the presence or suspicion of fungal, bacterial, viral or other infections that are uncontrolled or require treatment
• persons with central nervous system disorders caused by ADs or not caused by ADs.
• those with intolerable cardiac function;
• subjects with congenital immunoglobulin defects.
• history of malignant tumors within the last five years.
• end-stage renal failure;
• subjects with positive Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb) and peripheral blood HBV DNA titer higher than the upper limit of the test; subjects with positive antibody to Hepatitis C virus (HCV) and peripheral blood HCV RNA; subjects with positive antibody to Human Immunodeficiency Virus (HIV); and subjects with a positive test for Syphilis;
• mental illness and severe cognitive impairment;
• have participated in other clinical trials within 3 months prior to enrollment;
• immunosuppressants or biologics with a therapeutic effect for the indication within five half-lives prior to enrollment
• women who are pregnant or intend to become pregnant;
• subjects who, in the opinion of the investigator, have other reasons for not being included in the study.

Share IPD with The First Affiliated Hospital of China Medical University

The study will run from August 2025 to August 2027.

The sponsors and collaborators are able to access the IPD and supporting information, IPD relies on team collaboration , as well as continuous improvement in innovation and efficiency. Participants will share project information, including the project's objectives, statistical datas, and clinical study report.