Sikkerhed og effektivitet af universelle CD19-målrettede CAR-yΔT-celler i ildfast autoimmune sygdomme

Inclusion Criteria:

Common Inclusion Criteria:

1. Age between 18-80 years (inclusive), male or female.
2. Positive expression of CD19 on peripheral blood B cells by flow cytometry.
3. Diagnosed with refractory autoimmune disease, defined as: Ineffectiveness of conventional treatment for more than 6 months, or Disease activity recurrence after remission. Definition of conventional treatment: Use of glucocorticoids and any of the following immunosuppressants or biologics: cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, rituximab, belimumab, telitacicept, etc.
4. Currently receiving one or more standard therapies at a stable dose, including glucocorticoids, antimalarials, immunosuppressants, or biologics. If the subject is receiving glucocorticoids, the following conditions must be met: During screening and the screening period, the maximum dose of glucocorticoids is 30 mg/day prednisone (or an equivalent dose). The glucocorticoid dose must remain stable for ≥7 days before screening, and during the screening period, the dose adjustment must not exceed >5 mg/day prednisone (or an equivalent dose). If the subject is receiving antimalarials and/or conventional immunosuppressants: The treatment must have started ≥12 weeks before screening. The medication dose must remain stable for ≥8 weeks before screening and throughout the screening period. Before cell infusion, other immunosuppressants (excluding hydroxychloroquine), including belimumab, telitacicept, CD20 monoclonal antibodies, or other biologic immunosuppressants, must be discontinued for at least 5 half-lives.
5. Female participants of childbearing potential and male participants with female partners of childbearing potential must use medically approved contraceptive methods or practice abstinence during the study treatment period and for at least 6 months after the study. Female participants of childbearing potential must have a negative serum HCG test within 7 days before enrollment and must not be breastfeeding.
6. Willing to participate in the trial and sign the informed consent form.

Disease-Specific Inclusion Criteria:

1. Systemic Lupus Erythematosus (SLE):

   • Meets the 2019 EULAR/ACR classification criteria for SLE.
   • ANA titer ≥1:80, or positive for anti-dsDNA and/or anti-Sm antibodies.
   • Disease activity score (SLEDAI-2000) ≥8.

2. Sjögren's Syndrome:

   • Meets the 2002 AECG criteria or the 2016 ACR/EULAR classification criteria for primary Sjögren's syndrome.
   • Disease activity score (ESSDAI) ≥5.
   • Positive for anti-SSA/Ro antibodies.

3. Systemic Sclerosis (SSc):

   • Meets the 2013 EULAR/ACR classification criteria for systemic sclerosis.
   • Classified by Leroy and Medsger as limited or diffuse cutaneous subsets.
   • At screening, mRSS >10; and/or active interstitial lung disease (ILD), defined as: High-resolution computed tomography (HRCT) showing ground-glass opacities. Pulmonary function tests (FVC or DLCO) <70% of predicted values.

4. Idiopathic Inflammatory Myopathies (IIM):

   • Meets the 2017 EULAR/ACR classification criteria for inflammatory myopathies (including dermatomyositis, polymyositis, antisynthetase syndrome, and necrotizing myopathy).
   • For patients with muscle involvement: a. MMT-8 score <142 and at least two abnormal findings among the following core measures: PhGA or PtGA scores ≥2. Extramuscular disease activity score ≥2. HAQ total score ≥0.25. Muscle enzyme levels ≥1.5 times the upper normal limit. b. Alternatively, MMT-8 ≥142 but with active ILD (HRCT showing ground-glass opacities).
   • Positive for myositis-specific antibodies.

5. ANCA-Associated Vasculitis (AAV):

   • Meets the 2022 ACR/EULAR diagnostic criteria for ANCA-associated vasculitis, including microscopic polyangiitis, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis.
   • Positive for ANCA antibodies (current or historical).
   • Birmingham Vasculitis Activity Score (BVAS) ≥15 (out of 63), indicating active vasculitis.

6. Refractory Antiphospholipid Syndrome (APS):

   • Meets the 2023 ACR/EULAR diagnostic criteria for antiphospholipid syndrome.
   • Positive for medium-to-high titers of antiphospholipid antibodies (LA, anti-β2-GP1, or ACL IgG/IgM), with at least two positive results within 3 months.
   • Definition of refractory APS: Disease remains active or relapses after remission, despite 6 months of conventional therapy, including: Anticoagulants (warfarin or standard treatment with vitamin K antagonists maintaining target INR) or low-molecular-weight heparin at standard doses. Glucocorticoids and/or immunosuppressants.
   • Catastrophic APS (CAPS): Must meet all four criteria: a. Involvement of three or more organs, systems, and/or tissues. b. Symptoms occurring within one week. c. Histological evidence of small vessel occlusion in at least one organ or tissue. d. Positive for antiphospholipid antibodies (aPL).

Note: Meeting either criterion 3 or 4 is sufficient. Patients with thrombocytopenia may not require anticoagulant therapy.

Exclusion Criteria:

1. History of severe drug allergies or allergic constitution.
2. Presence or suspicion of uncontrolled or treatment-requiring fungal, bacterial, viral, or other infections.
3. Central nervous system (CNS) diseases caused by autoimmune or non-autoimmune conditions, including epilepsy, psychiatric disorders, organic brain syndrome, cerebrovascular accidents, encephalitis, or CNS vasculitis.
4. Dysfunction of major organs not meeting the following criteria (exceptions allowed if abnormalities are caused by autoimmune disease): a. Bone marrow function: White blood cell count ≥3×10⁹/L. Neutrophil count ≥1×10⁹/L (without GSF treatment within 2 weeks prior to testing). Hemoglobin ≥60 g/L. Platelet count ≥50×10⁹/L. b. Liver function: ALT ≤3×ULN (exceptions for ALT elevation caused by inflammatory myopathy). AST ≤3×ULN (exceptions for AST elevation caused by inflammatory myopathy). IBIL ≤1.5×ULN (exceptions for Gilbert's syndrome). Total bilirubin ≤3.0×ULN. c. Renal function: Creatinine clearance (CrCl) ≥30 mL/min (calculated using the Cockcroft/Gault formula, exceptions for acute CrCl decline caused by the disease itself). d. Coagulation function: International normalized ratio (INR) ≤1.5×ULN. Prothrombin time (PT) ≤1.5×ULN. e. Cardiac function: Stable hemodynamics.
5. Subjects with congenital immunoglobulin deficiencies.
6. History of malignancy within the past five years.
7. Subjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and peripheral blood HBV DNA levels exceeding the detection limit; positive hepatitis C virus (HCV) antibodies with detectable HCV RNA in peripheral blood; positive HIV antibodies; or positive syphilis test results.
8. Subjects with psychiatric disorders or severe cognitive impairment.
9. Participation in other clinical trials within 3 months prior to enrollment.
10. Previous treatment with CAR-T therapy.
11. History of severe adverse reactions to cyclophosphamide or fludarabine.
12. Any other reason that the investigator determine that subjects cannot be included in this study.