Overview

The objective of this study is to evaluate the efficacy and safety of BCMA/CD19 chimeric antigen receptor (CAR)-modified T cells in the treatment of autoimmune diseases.

Eligibility

Inclusion Criteria:

1. Age, 18-65 years old (inclusive), weight >=45kg, male and female;
2. The diagnosis of each disease meets the following criteria:

Systemic lupus erythematosus: 1997 ACR classification criteria or 2012 SLICC classification criteria Sjögren's syndrome: 2002 International Classification of Sjögren's Syndrome Inflammatory myopathies: 1977 Bohan Recommendation Systemic sclerosis: 1980 ACR classification criteria or 2013 ACR-EULAR classification criteria Behcet's disease: 1989 International Classification Criteria for Behcet's disease ANCA-associated vasculitis: 1990 ACR classification criteria IgG4-related disease: 2011 IgG4-RD composite diagnostic criteria Antiphospholipid syndrome: 2006 revision of the Sapporo APS classification criteria Acquired thrombotic thrombocytopenic purpura: consistent with a clinical diagnosis of TTP, including microscopic evidence of thrombocytopenia and red blood cell fragmentation (e.g., red blood cell fragmentation) 3. Multiple treatment regimens are ineffective or ineffective (including but not limited to high-dose glucocorticoids, adequate immunosuppressants and biologics) 4. Use of glucocorticoids (<=1mg/kg/d prednisone or equivalent doses of other hormones), DMARDs (such as methotrexate, hydroxychloroquine, azathioprine, mycophenolate mofetil, leflunomide, cyclosporine, etc.) must be on stable treatment for 4 weeks before receiving the first study drug, and no increase in hormone dose and other immunosuppressants throughout the study.

5. Subjects voluntarily participate in this study and voluntarily sign the informed

     consent form; 6. Subjects who have the possibility of having children or whose
     partners have the possibility of having children must agree to use effective
     contraception throughout the study period (but cannot use oral estrogen, use
     estrogen vaginal ring, etc.) 7. Additional enrollment criteria for different
     diseases (related to the degree of disease activity):

1. Patients with Behcet's disease must be active patients who meet the following conditions, and the active phase is defined as the emergence of new symptoms or the deterioration of existing symptoms, and one of the following conditions must be met:
   1. Organ involvement: involvement of any major organ (e.g., ocular lesions, vascular lesions, central nervous system, gastrointestinal system); B. 100% increase in the number of oral or genital ulcers >=compared to the onset of oral/genital ulcers compared to the first day; or an increase in the number of oral or genital ulcers by 3; C. Canker disease is at least 12 months; D. History of several oral ulcers per month E. Arthritis: >=50% increase in the number of swollen joints, or 3 more swollen joints; F. Skin lesions (non-oral/genital ulcers): >= physician overall lesion score increased by >=50% or by two points in the total score.
2. Patients with active inflammatory myopathy need to meet the following additional

   conditions

     Active myositis as defined by the Baseline Freehand Muscle Strength Test (MMT-8) of
     no more than 125/150 and at least 2 additional CSMs that meet the criteria specified
     below:
     a) Visual Analogue Scale[VAS] of patient global activity ≥2 cm, b) physician's
     global disease activity ≥2 cm, c) Health Assessment Questionnaire (HAQ) Disability
     Index ≥ 0.25 d) Elevation of at least one muscle enzyme [including creatine kinase
     (CK), aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and
     aspartate aminotransferase (AST)] with a minimum level of 1.3 x upper limit of
     normal e) Global Extramuscular Disease Activity Score, with a minimum of 1.0 cm on a
     10 cm VAS scale [This measure is a physician's comprehensive assessment based on the
     assessment of physique, skin, bone, gastrointestinal, lung, and cardiac activity
     scale activity scores using the Myositis Disease Activity Assessment Tool (MDAAT).
     f) To ensure that we are able to recruit patients with active DM with severe rash
     who may not meet the MMT-8 criteria above, we recommend the use of additional
     inclusion criteria so that the International Myositis Assessment and Clinical Study
     (IMACS) Improved Definition (DOI) can be achieved: 1) MDAAT > on the 10 cm VAS scale
     3 cm skin VAS score, and 2) at least 3 of the above 5 criteria.

3. ANCA-associated vasculitis:

1. Comply with GPA/MPA/EGPA classification standards; B. Patients with severe vasculitis activity (meeting at least one of the following conditions);
   1. Renal involvement is characterized by one of the following: i. Evidence of glomerulonephritis in any of the following situations: Renal biopsy shows focal necrotizing glomerulonephritis. Active urinary sediment characterized by glomerular hematuria and proteinuria ii. Patients with prior normal or no prior renal disease document, estimated glomerular filtration rate (eGFR) <50 ml/min/1.73 m2, and prior chronic kidney disease (eGFR <60 ml/min/1.73 m2) showed a reduction in eGFR of at least 25% compared with the previous one.
   2. Pulmonary hemorrhage due to active vasculitis satisfies all three of the following: i. Chest X-ray or CT scan showing diffuse pulmonary infiltrates ii. Pulmonary infiltrates that cannot be explained by other causes (e.g., volume overload or pulmonary infection) iii. At least one of the following: Evidence of alveolar hemorrhage on bronchoscopy or bloody bronchoalveolar lavage Hemoptysis was observed Unexplained anemia (<10 g/dL) or decreased hemoglobin (>1 g/dL) and less than 10g/dL Increased carbon dioxide dispersion
   3. Additional Enrollment Criteria for Systemic Sclerosis:

     Subjects are at high risk of fatal outcomes based on the following prognostic
     factors: Subjects must have the following "a" , and at least one of "b" or "c".
     a) Diffuse cutaneous scleroderma with an mRSS score of >=16, validated by the same
     physician at 2 different times >= 1 day apart and separated by < 28 days.
     b) Presence of SSc-related lung disease with FVC < 70% or 70% predicted DLCO < after
     hemoglobin correction and evidence of alveolitis obtained by high-resolution chest
     CT scan or PAL.
     c) History of SSc-related nephropathy, no disease activity before enrollment
     screening. A history of hypertensive renal crisis with scleroderma is included in
     this criterion and is defined as follows: i. History of new-onset hypertension based
     on any of the following (must be repeated and confirmed at least 2 hours apart
     within 3 days of the first event) with change from baseline SBP>=140 mmHg DBP>=90
     mmHg SBP rose by >=30 mmHg compared to baseline DBP increased by >=20 mmHg compared
     to baseline AND ii. One of the following 5 characteristics Serum creatinine
     increased >= >50% from baseline proteinuria: >=2+; Creatinine ratio > upper limit of
     normal Thrombocytopenia: <100, 000 plts/mm3 Hemolysis: increased by blood smear or
     reticulocyte count

5. Additional enrollment criteria for systemic lupus erythematosus A. The SLEDAI score

     of the patient before enrollment >= 7 points B. Failure to receive the following
     treatments: oral prednisone >=20 mg/d; Cyclophosphamide 0.4 to 0.6 g/m2 once every
     two weeks for 6 months, or other immunosuppressants such as mycophenolate mofetil 2
     g/day for 3 months without remission.

6. Additional enrollment criteria for antiphospholipid syndrome A. Cardiolipin

     antibody, lupus anticoagulant factor, and anti-β2-glycoprotein 1 antibody were all
     positive before enrollment.
     B. History of thromboembolism or morbid pregnancy confirmed by clear objective
     evidence.

7. Sjögren's disease additional enrollment criteria A. Positive anti-Ro/SSA antibody

screen. B. ESSDAI>= 6 POINTS

8. Additional enrollment criteria for IgG4-related diseases (confirmed: A+ B+C) A.

     Clinical examination showing the presence of characteristic diffuse/local swelling
     or masses in a single or multiple organs.

B. Blood tests show elevated serum IgG4 concentration (135 mg/dl). C. Histopathological examination shows significant lymphocytic and plasmacytic infiltration and fibrosis or IgG4+ plasmacyte infiltration (IgG4+/IgG+ cell ratio >40% and >10 IgG4+ plasma cells/HPF).

Exclusion Criteria:

1. Use of rituximab or other monoclonal antibodies within 1.6 months.
2. Received high-dose glucocorticoids (>1 mg/kg/d) within 1 month.
3. Serious complications: including heart failure (>= NYHA Class III), renal insufficiency (creatinine clearance <=30 ml/min), hepatic insufficiency (serum ALT or AST greater than three times the upper limit of normal, or total bilirubin greater than the upper limit of normal)
4. Other severe, progressive, or uncontrollable hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurological, or cerebral diseases (including demyelinating diseases such as multiple sclerosis).
5. Known allergies, hyperreactivity, or intolerance to IL-2 or its excipients.
6. Have a serious infection (including but not limited to hepatitis, pneumonia, bacteremia, pyelonephritis, Epstein-Barr virus, tuberculosis infection), or hospitalization for infection, or use of intravenous antibiotics for treatment of infection 2 months prior to the first dose of treatment.
7. Chest imaging showing malignancy or current activity within 3 months prior to the first use of study drug Abnormalities in sexually transmitted infections (including tuberculosis).
8. Infection with HIV (HIV antibody-positive serology) or hepatitis C (Hep C antibody-positive serology).

If seropositive, it is advisable to consult a physician with expertise in the treatment of HIV or hepatitis C virus infection.

10. Any known malignancy or history of malignancy within the past 5 years (with the

     exception of non-melanoma skin cancer, non-melanoma skin cancer with no signs of
     recurrence or surgically cured cervical tumor within 3 months prior to the use of
     the first investigational agent).

11. Have an uncontrolled mental or emotional disorder, including a history of drug and

     alcohol abuse within the past 3 years, which may preclude the successful completion
     of the study.

12. Received or anticipated receipt of any live viral or bacterial vaccine injection

     within 3 months prior to the first injection of study dose, during the study, or
     within 4 months after the last injection of study dose. Bacillus Calmette-Guérin
     vaccination within 12 months of screening.

13. Pregnant, lactating women (WCBP) who are unwilling to use medically approved

contraception during treatment and for 12 months after the end of treatment.

14. Males whose partner is of childbearing potential but who are unwilling to use

     appropriate medically approved contraception during treatment and for 12 months
     after the end of treatment.

15. Patients with inflammatory myopathies should additionally exclude: 3) Adolescent DM

     or PM, myositis overlaps with another connective tissue disease, cancer-associated
     myositis, inclusion body myositis, or any other non-immune-mediated myopathy.

4) Severe muscle impairment is defined as a baseline global muscle impairment score of

MDI (Myositis Injury Index) >=5cm on 10 cm VAS.

16. ANCA-associated vasculitis requires additional exceptions: positive anti-GBM

antibodies.