CD19-BCMA CART Cell Therapy for Refractory SLE-LN, SSc, and pSS-PAH

Inclusion Criteria 1. Refractory Lupus Nephritis（LN）: Patients who meet all the following requirements can be enrolled in the group. Definition: Failure to achieve induction remission after 3 to 6 months of treatment with at least one immunosuppressive agent (including glucocorticoids, cyclophosphamide \[CTX\], tacrolimus, mycophenolate mofetil, and cyclosporine), accompanied by no reduction (or worsening) in proteinuria or persistent positive autoantibodies. Diagnostic criteria : According to the 2019 American College of Rheumatology (ACR) criteria, and confirmed by renal biopsy in accordance with the 2018 International Society of Nephrology (ISN)/Renal Pathology Society (RPS) criteria (Appendix 3), were diagnosed with active, proliferative lupus nephritis (LN), including Class III or IV \[excluding Class III (C), IV-S (C), and IV-G (C)\], or combined Class III/IV with Class V. 1. Male or female, aged 10-65 years; 2. Meeting the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification Criteria for Systemic Lupus Erythematosus (Appendix 4); 3. The ANA result is positive which means ANA titer≥ 1:80 (based on the equivalent detection results by Hep-2 immunofluorescence assay or enzyme immune assay), and/or according to the detection results from center laboratory, during the screening visit,the anti dsDNA serum antibody test is positive (based on ELISA assay, ≥30 IU/mL); 4. B cell CD19+ expression, and stop using immunosuppressant more than one week. 5. The lymphocyte count in the subject's blood routine \>0.5×109/L, and no contraindications for cell collection; 6. No serious allergic constitution; 7. ECOG score: 0-2: 8. Expected survival ≥90 days: Subjects and/or their guardian can understand and sign the informed consent form. 2\. SSc: Patients who meet all the following requirements can be enrolled in the group. 1. Patients or their legal representatives sign the informed consent form; 2. Male or female, aged 18-65 years. 3. According to the SSc classification criteria proposed by American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR), chose the highest score under the same condition. If the score ≥9, it can be classified SSc. (Appendix 5) 4. Satisfy a sufficient condition: the skin on the fingers of both hands is thickened and extend to the proximal end of metacarpophalangeal joint; 5. The lymphocyte count in the subject's blood routine \>0.5×109/L, and no contraindications for cell collection. 3\. pSS-PAH: Patients who meet all the following requirements can be enrolled in the group. 1. Patients or their legal representatives sign the informed consent form; 2. Male or female, aged 18-65 years; 3. Refractory connective tissue disease (PAH)patients: a) Satisfy the 2002 AECG or 2016 ACR/2016 EULAR classification criteria, can be diagnosed as pSS (Appendix 6); b) Confirmed by Right heart catheterization, satisfy the diagnose criteria of PAH: mPAP at rest ≥20mmHg; PAWP≤15mmHg; PVR at rest\>2WUs. 4. Low-risk patients whose PAH do not reach the risk stratification. The patients should meet: WHO cardiac function grading I-II; 6 minutes walking distance\>440 m; BNP\<50ng/L or NT-proBNP\<300ng/L; RAP\<8mmHg and CI≥2.5 L·min-1·m-2; 5. Subjects have received standard treatment in stable dose before first use of study drug, include: Glucocorticoids (prednisone 0-30mg/day, or other equivalent preparations) ≥4 weeks; Antimalarial drugs, single-agent immunosuppressants (MMF≤1.5g/day, AZP or 6-MP≤2mg/kg/day, MTX≤15mg/week, Leflunomide ≤ 20mg/day) ≥12 weeks, and do not add or change in 24 weeks after drug treatment; Use PAH target drugs \<3 before drug treatment(PGAs, ETRA,PDE-5 inhibiter, GCCA), and stable at least 4 weeks, and do not add or change in 24 weeks after drug treatment; 6. After clinician evaluate the disease condition of patients, they will allow using glucocorticoids no more than 10mg or other equivalent dose and stop all immunosuppressants (exclued hydroxychloroquine); 7. Reproductive-aged female patients with negative blood human chorionic gonadotropin (HCG) test within 7 days before trial pre-conduct treatment; Any child-bearing male and female patients must agree to take effective contraceptive method during the process of study and within at least 1 year after cell infusion. Child-bearing patients refer that he or she has the biological ability to born alive baby and have normal sex life. Female patients without the ability of born: hysterectomy or ovariectomy, or medically confirmed ovarian failure, or medically confirmed postmenopausal (without pathological or biological reason, amenorrhea last for at least 12 months); 8. Have appropriate organ function, the criteria are as follows: a) AST≤3 times upper limit of normal (ULN); b) ALT ≤3 times ULN; c) T-Bil ≤2 times ULN, unless the patient has a record of Gilbert syndrome; Patients with Gilbert syndrome can be enrolled satisfied the condition of Bil≤3 times ULN and DBIl ≤1.5 times ULN; d) Must have the lowest level of lung reserve, oxygen saturation under non-oxygen inhalation state \>95%; e) The lymphocyte count in the subject's blood routine \>0.5×109/L, and no contraindications for cell collection. 4.AID Definition: Based on the reliable laboratory test, it is confirmed that one or more definite disease-related antibodies in serum are positive, laboratory results and clinical symptoms have reasonable association. Including systemic lupus erythematosus, sjogren's syndrome, systemic sclerosis, rheumatoid arthritis, connective tissue diseases, overlap syndrome, etc. At the same time exclude other etiology may cause similar symptoms and signs, infections, malignant tumors, metabolic diseases, primary organ failure, etc. 1. Male or female, aged 10-65 years; Patients who do not meet the inclusive criteria of three groups above, meet any one below can be enrolled. 2. ANA titer\<1:80 (based on the equivalent detection results by Hep-2 immunofluorescence assay or enzyme immune assay), and/or during the screening visit, by the detection results from center laboratory, anti dsDNA serum antibody test is negative (based on ELISA assay, \<30 IU/mL); 3. In conventional therapy, occur recurrent infections, leading to intolerance of conventional therapy, but no active infection, serious infection(tuberculosis) currently; 4. Patients who cannot use drugs anymore, because of bone infarction, osteonecrosis, severe bone pain caused by long term use of drugs. 5. Patients who cannot use drugs anymore, because of vision changes, retinopathy, fundus hemorrhage caused by long term use of drugs. 6. Patients who cannot use drugs anymore, because of endocrine-related changes (premature closure of the femoral shaft, severe obesity, diabetes, impact on growth and development, etc.) caused by long term use of drugs. 7. Severe toxicity of blood system (≥grade3; neutrophil\<1\*10\^9/L,platelet\<50\*10\^9/L,hemoglobin\<80g/L); 8. Abnormal liver function (ALT ≥3 times ULN; ALT≥3 times ULN; T-Bil ≥2 times ULN); 9. After 3 months of regular treatment, there are still have disease progression (eg. urine protein index increased by 3 times); 10. Previously received CAR-T therapies, there are still have disease progression. Exclusion criteria: An individual who meets any of the following criteria will be excluded from participation in this study: 1\. Refractory Lupus Nephritis (LN): 1. Intracranial hypertension or disorder of consciousness; 2. Symptomatic heart failure or severe arrhythmia; 3. Symptoms of severe respiratory failure; 4. Complicated with other types of malignant tumors; 5. Diffuse intravascular coagulation; 6. Suffering from septicemia or other uncontrollable infections; 7. Patients with uncontrollable diabetes and other endocrine diseases; 8. Severe mental disorders; 9. Obvious and active intracranial lesions were detected by cranial magnetic resonance imaging (MRI); 10. Have received organ transplantation (excluding bone marrow transplant); 11. Reproductive-aged female patients with positive blood human chorionic gonadotropin (HCG) test; 12. Positive screening for hepatitis (HBV and HCV included), HIV and syphilis; 13. The subject is unable to undergo PBMC collection, nor are there cryopreserved PBMCs available for CAR-T cell manufacturing; 14. eGFR CKD-EPI \< 30 ml/min/1.73m\^2; 15. Any active skin disease that may interfere with the assessment of systemic lupus erythematosus (SLE) research, including but not limited to psoriasis, dermatomyositis, systemic sclerosis, non-SLE cutaneous manifestations (e.g., cutaneous vasculopathy, perivascular telangiectasia, sclerodactyly, rheumatoid nodules, erythema multiforme, leg ulcers), or drug-induced lupus; 16. Previously received other CAR-T therapies except CD19-CART. 2.SSc 1. Other connective tissue disease: Rheumatoid Arthritis, System Lupus or Inflammatory Myopathies; 2. Clinical manifestations can be explained by disease similar to SSc: hand joint lesions related to nephrogenic systemic fibrosis, generalized morphea, eosinophilic fasciitis, diabetic scleredema, scleromyxedema, erythromelalgia, porphyria, lichen sclerosus, graft-versus-host disease, diabetes mellitus, and other endocrine and metabolic diseases; 3. Patients who have severe active central nervous system (CNS) lupus, including epileptic seizures, pyschosis, cerebrovascular accident or CNS vasculitis requiring treatment intervention within 60 days after baseline; 4. Dialysis patients or Ccr \<30ml/min; 5. Pregnant or suckling period; 6. Combined with active infection (eg. septicemia, bacteremia, fungemia, uncontrolled pulmonary infection, and active tuberculosis); 7. Detection positive: HBsAg, HbeAg; HBe-Ab, HBc-Ab (the copy number of HBV-DNA is greater than the measurable low limit); HCV-Ab, HIV-Ab, TP-Ab; 8. Patients have undergone big surgeries which evaluated by investigators as unsuitable for enrollment within 4 weeks before screening; 9. Previously received other CAR-T therapies except CD19-CART. 3.pSS-PAH 1. PH caused by other reasons: Portal hypertension, hereditary hemorrhagic telangiectasia, etc.; congenital heart disease; suspected drugs and toxicants; pulmonary hypertension related to chronic hypoxic diseases: moderate or severe obstructive pulmonary disease: FEV1 \< 55%; moderate or severe restrictive pulmonary disease: TLC \< 60%; pulmonary hypertension due to chronic thromboembolic disease: pulmonary ventilation/perfusion imaging suggests moderate or high suspicion of pulmonary thromboembolism; 2. Patients who have severe active central nervous system (CNS) lupus, including epileptic seizures, pyschosis, cerebrovascular accident or CNS vasculitis requiring treatment intervention within 60 days after baseline; 3. Dialysis patients or Ccr \<30ml/min; 4. Pregnant or suckling period; 5. Combined with active infection (eg. septicemia, bacteremia, fungemia, uncontrolled pulmonary infection, and active tuberculosis). 6. Detection positive: HBsAg, HbeAg; HBe-Ab, HBc-Ab (the copy number of HBV-DNA is greater than the measurable low limit); HCV-Ab, HIV-Ab, TP-Ab; 7. Patients have undergone big surgeries which evaluated by investigators as unsuitable for enrollment within 4 weeks before screening; 8. Previously received other CAR-T therapies except CD19-CART. 6\) Detection positive: HBsAg, HbeAg; HBe-Ab, HBc-Ab (the copy number of HBV-DNA is greater than the measurable low limit); HCV-Ab, HIV-Ab, TP-Ab; 7) Patients have undergone big surgeries which evaluated by investigators as unsuitable for enrollment within 4 weeks before screening; 8) Previously received other CAR-T therapies except CD19-CART. 4. AID 1. Intracranial hypertension or disorder of consciousness; 2. Symptomatic heart failure or severe arrhythmia; 3. Symptoms of severe respiratory failure; 4. Complicated with other types of malignant tumors; 5. Diffuse intravascular coagulation; 6. Suffering from septicemia or other uncontrollable infections; 7. Patients with uncontrollable diabetes and other endocrine diseases; 8. Severe mental disorders; 9. Obvious and active intracranial lesions were detected by cranial magnetic resonance imaging (MRI); 10. Have received organ transplantation (excluding bone marrow transplant); 11. Reproductive-aged female patients with positive blood human chorionic gonadotropin (HCG) test; 12. Positive screening for hepatitis (HBV and HCV included), HIV and syphilis; 13. The subject is unable to undergo PBMC collection, nor are there cryopreserved PBMCs available for CAR-T cell manufacturing; 14. eGFR CKD-EPI \< 30 ml/min/1.73m\^2.