Anti-CD19-CD3E-CAR-T Cells in Relapsed/Refractory Autoimmune Disease

Step 1. Assessment of eligibility for Enrollment Inclusion Criteria for Enrollment Common Inclusion Criteria:

1. Age between 18 and 65 years old (inclusive), regardless of gender.
2. Positive expression of CD19 on peripheral blood B cells confirmed by flow cytometry.
3. Functional requirements for major organs are as follows: 1) Bone marrow function mustmeet: A. Neutrophil count ≥ 1×109/L (no colony-stimulating factor treatment within 2weeks before examination); B. Hemoglobin ≥ 60g/L; 2) Liver function: Alanineaminotransferase (ALT) ≤ 3×ULN (excluding ALT elevation due to inflammatory myopathy),aspartate aminotransferase (AST)≤3×Upper limit of normal (ULN) (excluding ASTelevation due to inflammatory myopathy), TBIL≤1.5×ULN (or ≤ 3.0×ULN for subjects withGilbert syndrome); 3) Renal function: creatinine clearance rate (CrCl) ≥ 30ml/minute (calculated by Cockcroft/Gault formula, acute CrCl decrease due to the target diseaseis excluded); 4) Coagulation function: International standardized ratio (INR) <1.5×ULN, prothrombin time (PT) <1.5×ULN; 5) Cardiac function: Stable hemodynamic.
4. Female subjects of childbearing potential and male subjects with partners ofchildbearing potential must use medically approved contraception or abstinence duringthe study treatment period and for at least 6 months after the end of the studytreatment; Female subjects of childbearing potential must have a negative Humanchorionic gonadotropin (HCG) test within 7 days before study enrollment and not belactating.
5. Willing to participate in this clinical study, sign an informed consent form, havegood compliance, and cooperate with follow-up. Disease-Specific Inclusion Criteria Refractory/Relapsed SLE:
6. SLE fulfilling the 2019 the American College of Rheumatology (ACR) /European LeagueAgainst Rheumatism (EULAR) and classification criteria.
7. Systemic lupus erythematosus disease activity index (SLEDAI)-2000 score ≥ 6 with atleast one BILAG (British Isle Lupus Rating Group Index 2004) A or two BILAG B; orSLEDAI-2000 score ≥ 8.
8. Definition of relapsed/refractory: Conventional treatment over 6 months remainsineffective, or disease recurrence after remission. Definition of conventionaltreatment: the use of glucocorticoids and cyclophosphamide, and any one or more of thefollowing immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil,methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics includingbelimumab, rituximab, and tocilizumab, etc. Refractory/Relapsed Sjogren's syndrome:
9. Primary Sjogren's syndrome fulfilling the 2002 AECG criteria or the 2016 ACR/EULARclassification criteria.
10. EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥ 6
11. Positive anti-SSA/Ro antibodies
12. Definition of relapsed/refractory: Conventional treatment over 6 months remainsineffective, or disease recurrence after remission. Definition of conventionaltreatment: the use of glucocorticoids and cyclophosphamide, and any one or more of thefollowing immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil,methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics includingbelimumab, rituximab, and tocilizumab, etc. Refractory/Relapsed/Progressive Systemic Sclerosis:
13. Scleroderma fulfilling the 2013 ACR classification criteria
14. Positive scleroderma-related antibodies.
15. Presence of diffuse cutaneous sclerosis or active interstitial lung disease (high-resolution computed tomography (HRCT) showing ground-glass opacities);
16. Definition of relapsed/refractory: Conventional treatment over 6 months remainsineffective, or disease recurrence after remission. Definition of conventionaltreatment: the use of glucocorticoids and cyclophosphamide, and any one or more of thefollowing immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil,methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics includingbelimumab, rituximab, and tocilizumab, etc.
17. Definition of progressive: Rapid skin progression (mRSS increase > 25%); orprogression of lung disease (forced vital capacity (FVC) decrease by 10%, or FVCdecrease by more than 5% with diffusing capacity of the lung for carbon monoxide (DLCO) decrease by 15%). Note: Meeting either criterion 4 or 5 is sufficient. Refractory/Relapsed/Progressive Inflammatory Myopathy:
18. Inflammatory myopathy fulfilling the 2017 EULAR/ACR classification criteria (includingDermatomyositis (DM), Polymyositis (PM), Anti-Synthetase Syndrome (ASS), andNecrotizing Myopathy (NM)).
19. Positive myositis antibodies;
20. Muscle involvement with Manual Muscle Testing-8 (MMT-8) score less than 142 and atleast two abnormalities found among the following five core measurements (PhysicianGlobal Assessment (PhGA), Patient Global Assessment (PtGA), or extramuscular diseaseactivity score ≥ 2; Health Assessment Questionnaire (HAQ) total score ≥ 0.25; muscleenzyme levels ≥ 1.5×ULN; or MMT-8 ≥ 142, but with active interstitial lung disease (HRCT showing ground-glass opacities);
21. Definition of relapsed/refractory: Conventional treatment over 6 months remainsineffective, or disease recurrence after remission. Definition of conventionaltreatment: the use of glucocorticoids and cyclophosphamide, and any one or more of thefollowing immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil,methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics includingbelimumab, rituximab, and tocilizumab, etc.
22. Definition of progressive: Rapid progression of interstitial lung disease within ashort period. Note: Meeting either criterion 4 or 5 is sufficient. Refractory/Relapsed ANCA-Associated Vasculitis:
23. ANCA-Associated Vasculitis fulfilling 2022 ACR/EULAR criteria, including microscopicpolyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis withpolyangiitis.
24. Positive ANCA-associated antibodies (MPO-ANCA or PR3-ANCA positive).
25. The Birmingham Vasculitis Activity Scale (BVAS) ≥ 15 points (a total score of 63points), indicating active vasculitis.
26. Definition of refractory/relapsed: Conventional treatment over 6 months remainsineffective, or disease recurrence after remission., or disease recurrence afterremission. Definition of conventional treatment: the use of glucocorticoids andcyclophosphamide, and any one or more of the following immunomodulatory drugs:antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide,tacrolimus, cyclosporine, and biologics including belimumab, rituximab, andtocilizumab, etc. Refractory/Relapsed/Catastrophic Antiphospholipid Syndrome:
27. Primary antiphospholipid syndrome fulfilling 2006 Sydney criteria.
28. Positive phospholipid antibodies with medium to high titers (IgG/IgM for LupusAnticoagulant (LA), Beta-2 Glycoprotein 1 (B2GP1), or Anticardiolipin (aCL), positivemore than twice within 12 weeks).
29. Definition of refractory/relapsed: Standard treatment with warfarin anticoagulation oralternative vitamin K antagonist therapy (maintaining treatment-required INR) orstandard therapeutic dose of low molecular weight heparin (LMWH) and use of steroidsand cyclophosphamide for recurrent thrombosis;
30. Catastrophic antiphospholipid syndrome needs to meet the following four criteria: (1)involvement of three or more organs, systems, and/or tissues; (2) symptoms occurringwithin one week; (3) histological confirmation of small vessel occlusion in at leastone organ or tissue; (4) positive aPL antibodies. Note: Meeting either criterion 3 or 4 is sufficient.

Exclusion Criteria:

1. Subjects with a history of severe drug allergies or allergic tendencies;
2. Presence or suspicion of uncontrolled or treatment-required fungal, bacterial, viral,or other infections;
3. Subjects with central nervous system diseases caused by autoimmune diseases ornon-autoimmune diseases (including epilepsy, psychosis, organic brain syndrome,cerebral vascular accidents, encephalitis, central nervous system vasculitis);
4. Subjects with insufficient cardiac function;
5. Subjects with congenital immunoglobulin deficiencies;
6. History of malignancy within five years;
7. Subjects with end-stage renal failure;
8. Subjects who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B coreantibody (HBcAb) with peripheral blood HBV DNA >ULN; subjects positive for hepatitis Cvirus (HCV) antibody and peripheral blood HCV RNA; individuals positive for humanimmunodeficiency virus (HIV) antibody; individuals positive for syphilis testing;
9. Subjects with psychiatric disorders and severe cognitive impairments;
10. Subjects who have participated in other clinical trials within the past 3 months priorto enrollment;
11. Subjects who have received biologics with therapeutic effects for indications within 4weeks prior to enrollment;
12. Subjects who have received immunosuppressive agents with therapeutic effects forindications within 2 weeks prior to enrollment;
13. Subjects who have received >10mg/d prednisone or equivalent dose of other steroidswithin 2 weeks prior to enrollment;
14. Pregnant women or women planning to conceive;
15. Subjects whom the investigator believes have other reasons that make them unsuitablefor inclusion in this study. Step 2. Assessment of eligibility for CAR-T Cells Infusion Inclusion Criteria
16. Completion of Step 1 and successful preparation of CAR-T cell product;
17. Adequate organ function, defined as: 1) Creatinine clearance rate (Cockcroft andGault) >30 mL/min/1.73 m2, excluding acute decrease in CrCl due to the target disease;

2. ALT/AST ≤ 3×ULN (excluding liver enzyme elevation caused by inflammatory diseases);TBIL ≤ 1.5×ULN (Gilbert's syndrome allows TBIL ≤ 3×ULN). Exclusion Criteria

1. Systemic fungal, bacterial, viral, or other infection that is not controlled (definedas exhibiting ongoing signs/symptoms related to the infection and without improvement,despite appropriate antibiotics or other treatment);
2. >10mg/d prednisone or equivalent dose of other steroids within 72 hours prior to CAR-Tinfusion.