Universal CAR-T Cells (BRL-301) in Relapse or Refractory Autoimmune Diseases

Common Inclusion Criteria:

• Age ranges from 18 to 65 years old (including threshold), regardless of gender.

• Positive expression of CD19 on peripheral blood B cells determined by flowcytometry.

• The functions of important organs meet the following requirements:

1. Bone marrow hematopoietic function needs to meet: a. White blood cell count ≥ 3x 10^9/L b. Neutrophil count ≥ 1 x 10^9/L (no colony-stimulating factortreatment within 2 weeks before examination); c. Hemoglobin ≥60g/L.

2. Liver function:ALT ≤ 3 x ULN,AST≤3 x ULN, TBIL≤1.5 x ULN(excluding Gilbertsyndrome, total bilirubin ≤ 3.0 x ULN) (No requirements for conditions causedby the disease itself).

3. Renal function: creatinine clearance rate (CrCl) ≥ 60 ml/minute(Cockcroft/Faultformula).

4. Coagulation function: International standardized ratio (INR) < 1.5 xULN,prothrombin time(PT) < 1.5 x ULN.

5. Cardiac function: Good hemodynamic stability.

• Female subjects with fertility and male subjects whose partners are women ofchildbearing age are required to use medically approved contraception or abstinenceduring the study treatment period and at least 6 months after the end ofthe studytreatment period; Female subjects of childbearing age tested negative for serum HCGwithin 7 days before enrollment in the study and were not in lactation.

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

Criteria for SLE:

• Complies with the classification standards of the 2019 European Union AgainstRheumatology/American Society of Rheumatology (EULAR/ACR) SLE.

• In the moderate to severe active phase of the disease, with SLEDAI-2000 score>6.

• And at least one British Isle Lupus Rating Group Index (BILAG-2004) Class A (severemanifestation) or two Class B (moderate manifestation) organ scores, or both.

• Ineffective conventional treatment or relapse of disease activity after remission.Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) andcyclophosphamide, as well as any of the following immunomodulatory drugs for morethan 6 months: antimalarial drugs, azathioprine, mycophenolate mofetil,methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biological agentssuch as rituximab, belimumab and telitacicept.

Criteria for Sjogren's syndrome with thrombocytopenia:

• Meets the 2002 AECG criteria for primary Sjogren's syndrome or the 2016 ACR/EULARclassification criteria.

• Diagnosed pSS-TP, platelet count < 30 × 10^9/L.

• Ineffective conventional treatment or relapse of disease activity after remission.Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) andcyclophosphamide, as well as any of the following immunomodulatory drugs for morethan 6 months: antimalarial drugs, azathioprine, mycophenolate mofetil,methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biological agentssuch as rituximab and belimumab.

Criteria for Systemic Sclerosis:

• Meets the classification criteria for Systemic Sclerosis according to the 2013 ACR,and conforms to diffuse manifestations.

• Concomitant interstitial pneumonia: interstitial changes with ground glass likeexudate detected by chest HRCT.

• Needs to be met 1. or 2.:

1. Ineffective conventional treatment or relapse of disease activity afterremission. Definition of routine treatment: Use of glucocorticoids (above 0.5mg/Kg/d) and cyclophosphamide, as well as any of the followingimmunomodulatory drugs for more than 6 months: antimalarial drugs,azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus,cyclosporine, as well as biological agents such as rituximab and belimumab.

2. Definition of progressiveness: a) Definition of skin progression: mRSSincreases by>25%; b) The definition of lung disease progression: a 10% decreasein FVC, or a 5% decrease in FVC accompanied by a 15% decrease in DLCO.

Criteria for Inflammatory Myopathy:

• Classification criteria for inflammatory myopathy in accordance with 2017 EULAR/ACR (including DM, PM, ASS, and NM).

• For those with muscle involvement, the MMT-8 score is lower than 142 and at leasttwo abnormalities are found in the following five core measurements (PhGA, PtGA, orextramuscular disease activity score ≥ 2 points; total HAQ score ≥ 0.25; muscleenzyme levels are 1.5 times the upper limit of the normal range).

• Myositis antibody positive.

• Needs to be met 1.or 2.:

1. Ineffective conventional treatment or relapse of disease activity afterremission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the followingimmunomodulatory drugs for more than 6 months: antimalarial drugs,azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus,cyclosporine, as well as biological agents such as rituximab and belimumab.

2. Progressive definition: rapid progression of interstitial pneumonia in a shortperiod of time.

Criteria for ANCA Associated Vasculitis:

• Meets the diagnostic criteria for ANCA vasculitis in 2022 ACR/EULAR, includingmicroscopic polyangitis, granulomatous polyangitis, and eosinophilic granulomatouspolyangitis.

• Positive ANCA related antibodies (MPO-ANCA or PR3-ANCA positive).

• The Birmingham Vasculitis Activity Scale (BVAS) is ≥ 15 points (a total score of 63points), indicating the activity of the vasculitis condition.

• There must be at least one main item, at least three secondary items, or at leasttwo renal items, hematuria and proteinuria, in the BVAS evaluation.

• Ineffective conventional treatment or relapse of disease activity after remission.Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) andcyclophosphamide, as well as any of the following immunomodulatory drugs for morethan 6 months: antimalarial drugs, azathioprine, mycophenolate mofetil,methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biological agentssuch as rituximab and belimumab.

Criteria for Antiphospholipid syndrome:

• Meets the diagnostic criteria for primary antiphospholipid syndrome revised inSydney in 2006.

• Positive phospholipid antibodies with medium to high titers (IgG/IgM for LA, B2GP1,or acL, tested more than twice within 12 weeks).

• Needs to be met 1. or 2.:

1. Use warfarin anticoagulation or replace the standard treatment of vitamin Kantagonist (i.e. maintain the INR required for treatment) or use the standardtreatment dose of low molecular weight heparin (LMWH), as well as use ofhormones and cyclophosphamide to treat relapse thrombosis.

2. Catastrophic antiphospholipid syndrome requires the following four criteria: (1) involving three or more organs, systems, and/or tissues; (2) Symptomsappear within 1 week; (3) Histologically confirmed obstruction of small bloodvessels in at least one organ or tissue; (4) APL positive.

Exclusion Criteria:

• Individuals with a history of severe drug allergies or allergic constitution.

• Existence or suspicion of uncontrollable or treatable fungal, bacterial, viral orother infections.

• Individuals with relatively serious heart diseases, such as angina pectoris,myocardial infarction, heart failure, and arrhythmia.

• Subjects with congenital immunoglobulin deficiency.

• Other malignant tumors (excluding non-melanoma skin cancer, cervical cancer in situ,bladder cancer and breast cancer that have survived for more than 5 years withoutdisease).

• Subjects with end-stage renal failure.

• Subjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B coreantibody (HBcAb) and HBV DNA titer in peripheral blood higher than the upper limitof detection; Patients with positive hepatitis C virus (HCV) antibodies and positiveperipheral blood HCV RNA; People who are positive for human immunodeficiency virus (HIV) antibodies; Those who have tested positive for syphilis.

• Having mental illness and severe cognitive impairment.

• Those who have participated in other clinical trials within the first 3 months ofenrollment.

• Pregnant or intending to conceive women.

• The researchers believe that there are other reasons why subjects cannot be includedin this study.