Overview
This is an investigator-initiated trial to evaluate the safety and efficacy of anti-CD19-CD3E-CAR-T cells in the relapse or refractory autoimmune diseases.
Description
This is an investigator-initiated trial to evaluate the safety and efficacy of anti-CD19-CD3E-CAR-T cells in the relapse or refractory autoimmune diseases.
Study intervention consists of a single infusion of CAR-transduced autologous T cells administered intravenously after a lymphodepleting therapy regimen consisting of fludarabine and cyclophosphamide.
Interim analysis will be performed when participants finish the visit of 12 weeks after CAR-T cells infusion.
Eligibility
Step 1. Assessment of eligibility for Enrollment Inclusion Criteria for Enrollment
Common Inclusion Criteria:
- Age between 18 and 65 years old (inclusive), regardless of gender.
- Positive expression of CD19 on peripheral blood B cells confirmed by flow cytometry.
- Functional requirements for major organs are as follows: 1) Bone marrow function must meet: A. Neutrophil count ≥ 1×109/L (no colony-stimulating factor treatment within 2 weeks before examination); B. Hemoglobin ≥ 60g/L; 2) Liver function: Alanine aminotransferase (ALT) ≤ 3×ULN (excluding ALT elevation due to inflammatory myopathy), aspartate aminotransferase (AST)≤3×Upper limit of normal (ULN) (excluding AST elevation due to inflammatory myopathy), TBIL≤1.5×ULN (or ≤ 3.0×ULN for subjects with Gilbert syndrome); 3) Renal function: creatinine clearance rate (CrCl) ≥ 30ml/minute (calculated by Cockcroft/Gault formula, acute CrCl decrease due to the target disease is excluded); 4) Coagulation function: International standardized ratio (INR) <1.5×ULN, prothrombin time (PT) <1.5×ULN; 5) Cardiac function: Stable hemodynamic.
- Female subjects of childbearing potential and male subjects with partners of childbearing potential must use medically approved contraception or abstinence during the study treatment period and for at least 6 months after the end of the study treatment; Female subjects of childbearing potential must have a negative Human chorionic gonadotropin (HCG) test within 7 days before study enrollment and not be lactating.
- Willing to participate in this clinical study, sign an informed consent form, have good compliance, and cooperate with follow-up.
Disease-Specific Inclusion Criteria
Refractory/Relapsed SLE:
- SLE fulfilling the 2019 the American College of Rheumatology (ACR) /European League Against Rheumatism (EULAR) and classification criteria.
- Systemic lupus erythematosus disease activity index (SLEDAI)-2000 score ≥ 6 with at least one BILAG (British Isle Lupus Rating Group Index 2004) A or two BILAG B; or SLEDAI-2000 score ≥ 8.
- Definition of relapsed/refractory: Conventional treatment over 6 months remains ineffective, or disease recurrence after remission. Definition of conventional treatment: the use of glucocorticoids and cyclophosphamide, and any one or more of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc.
Refractory/Relapsed Sjogren's syndrome:
- Primary Sjogren's syndrome fulfilling the 2002 AECG criteria or the 2016 ACR/EULAR classification criteria.
- EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥ 6
- Positive anti-SSA/Ro antibodies
- Definition of relapsed/refractory: Conventional treatment over 6 months remains ineffective, or disease recurrence after remission. Definition of conventional treatment: the use of glucocorticoids and cyclophosphamide, and any one or more of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc.
Refractory/Relapsed/Progressive Systemic Sclerosis:
- Scleroderma fulfilling the 2013 ACR classification criteria
- Positive scleroderma-related antibodies.
- Presence of diffuse cutaneous sclerosis or active interstitial lung disease (high-resolution computed tomography (HRCT) showing ground-glass opacities);
- Definition of relapsed/refractory: Conventional treatment over 6 months remains ineffective, or disease recurrence after remission. Definition of conventional treatment: the use of glucocorticoids and cyclophosphamide, and any one or more of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc.
- Definition of progressive: Rapid skin progression (mRSS increase > 25%); or progression of lung disease (forced vital capacity (FVC) decrease by 10%, or FVC decrease 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:
- Inflammatory myopathy fulfilling the 2017 EULAR/ACR classification criteria (including Dermatomyositis (DM), Polymyositis (PM), Anti-Synthetase Syndrome (ASS), and Necrotizing Myopathy (NM)).
- Positive myositis antibodies;
- Muscle involvement with Manual Muscle Testing-8 (MMT-8) score less than 142 and at least two abnormalities found among the following five core measurements (Physician Global Assessment (PhGA), Patient Global Assessment (PtGA), or extramuscular disease activity score ≥ 2; Health Assessment Questionnaire (HAQ) total score ≥ 0.25; muscle enzyme levels ≥ 1.5×ULN; or MMT-8 ≥ 142, but with active interstitial lung disease (HRCT showing ground-glass opacities);
- Definition of relapsed/refractory: Conventional treatment over 6 months remains ineffective, or disease recurrence after remission. Definition of conventional treatment: the use of glucocorticoids and cyclophosphamide, and any one or more of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc.
- Definition of progressive: Rapid progression of interstitial lung disease within a short period.
Note: Meeting either criterion 4 or 5 is sufficient.
Refractory/Relapsed ANCA-Associated Vasculitis:
- ANCA-Associated Vasculitis fulfilling 2022 ACR/EULAR criteria, including microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis.
- Positive ANCA-associated antibodies (MPO-ANCA or PR3-ANCA positive).
- The Birmingham Vasculitis Activity Scale (BVAS) ≥ 15 points (a total score of 63 points), indicating active vasculitis.
- Definition of refractory/relapsed: Conventional treatment over 6 months remains ineffective, or disease recurrence after remission., or disease recurrence after remission. Definition of conventional treatment: the use of glucocorticoids and cyclophosphamide, and any one or more of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc.
Refractory/Relapsed/Catastrophic Antiphospholipid Syndrome:
- Primary antiphospholipid syndrome fulfilling 2006 Sydney criteria.
- Positive phospholipid antibodies with medium to high titers (IgG/IgM for Lupus Anticoagulant (LA), Beta-2 Glycoprotein 1 (B2GP1), or Anticardiolipin (aCL), positive more than twice within 12 weeks).
- Definition of refractory/relapsed: Standard treatment with warfarin anticoagulation or alternative vitamin K antagonist therapy (maintaining treatment-required INR) or standard therapeutic dose of low molecular weight heparin (LMWH) and use of steroids and cyclophosphamide for recurrent thrombosis;
- Catastrophic antiphospholipid syndrome needs to meet the following four criteria: (1) involvement of three or more organs, systems, and/or tissues; (2) symptoms occurring within one week; (3) histological confirmation of small vessel occlusion in at least one organ or tissue; (4) positive aPL antibodies.
Note: Meeting either criterion 3 or 4 is sufficient.
Exclusion Criteria:
- Subjects with a history of severe drug allergies or allergic tendencies;
- Presence or suspicion of uncontrolled or treatment-required fungal, bacterial, viral, or other infections;
- Subjects with central nervous system diseases caused by autoimmune diseases or non-autoimmune diseases (including epilepsy, psychosis, organic brain syndrome, cerebral vascular accidents, encephalitis, central nervous system vasculitis);
- Subjects with insufficient cardiac function;
- Subjects with congenital immunoglobulin deficiencies;
- History of malignancy within five years;
- Subjects with end-stage renal failure;
- Subjects who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA >ULN; subjects positive for hepatitis C virus (HCV) antibody and peripheral blood HCV RNA; individuals positive for human immunodeficiency virus (HIV) antibody; individuals positive for syphilis testing;
- Subjects with psychiatric disorders and severe cognitive impairments;
- Subjects who have participated in other clinical trials within the past 3 months prior to enrollment;
- Subjects who have received biologics with therapeutic effects for indications within 4 weeks prior to enrollment;
- Subjects who have received immunosuppressive agents with therapeutic effects for indications within 2 weeks prior to enrollment;
- Subjects who have received >10mg/d prednisone or equivalent dose of other steroids within 2 weeks prior to enrollment;
- Pregnant women or women planning to conceive;
- Subjects whom the investigator believes have other reasons that make them unsuitable for inclusion in this study.
Step 2. Assessment of eligibility for CAR-T Cells Infusion Inclusion Criteria
- Completion of Step 1 and successful preparation of CAR-T cell product;
- Adequate organ function, defined as: 1) Creatinine clearance rate (Cockcroft and Gault) >30 mL/min/1.73 m2, excluding acute decrease in CrCl due to the target disease;
- 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
- Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment);
- >10mg/d prednisone or equivalent dose of other steroids within 72 hours prior to CAR-T infusion.