car t-cell therapy targeting cd19 and bcma in patients with relapse/refractory autoimmune diseases

Conditions: SLE; Systemic Sclerosis (SSc); Inflammatory Myopathy; ANCA-Associated Vasculitis (AAV)

Summary: car t-cell therapy targeting cd19 and bcma in patients with relapse/refractory autoimmune diseases

this is an investigator-initiated trial to evaluate the safety and efficacy ofuniversal allogeneic anti-cd19/bcma car t-cells in patients with relapse/refractory autoimmune diseases. study intervention consists of a single infusion of universal allogeneic cart-cells administered intravenously after a lymphodepleting therapy regimen consisting of fludarabine and cyclophosphamide. interim analysis will be performed when participants finish the visit 12 and 24 weeks after car t-cell infusion.

Eligibility criteria:
inclusion criteria: common inclusion criteria: 1. age ≥ 18 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 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; ln is exluded); 4. ecog score 0-1. 5. 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. 6. 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: 1. sle fulfilling the 2019 the american college of rheumatology (acr) /european league against rheumatism (eular) and classification criteria. 2. sledai-2000 score ≥ 8. 3. the diagnosis of lupus nephritis was confirmed with renal biopsy within 6 months before the study, and histological diagnosis (ln classification of isn/rps in 2018) was active nephritis type iii or iv with or without type v.nih activity index (ai)\>2, chronic index (ci) is elevated ; urine protein to creatinine ratio (upcr)\>1.0g/g, or 24-hour urine protein\>1.0g, with or without active urinary sediment with erythrocyte precipitation. 4. 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: 1. scleroderma fulfilling the 2013 acr classification criteria 2. positive scleroderma-related antibodies. 3. presence of diffuse cutaneous sclerosis or active interstitial lung disease (high-resolution computed tomography (hrct) showing ground-glass opacities); 4. 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 any one or more of the following immunomodulatory drugs: cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc. 5. 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: 1. inflammatory myopathy fulfilling the 2017 eular/acr classification criteria (including dermatomyositis (dm), polymyositis (pm), anti-synthetase syndrome (ass), and necrotizing myopathy (nm)). 2. 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); 3. 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 any one or more of the following immunomodulatory drugs: cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc. 4. 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: 1. anca-associated vasculitis fulfilling 2022 acr/eular criteria, including microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis. 2. positive anca-associated antibodies (mpo-anca or pr3-anca positive). 3. the birmingham vasculitis activity scale (bvas) ≥ 15 points (a total score of 63 points), indicating active vasculitis. 4. 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 any one or more of the following immunomodulatory drugs: cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including belimumab, rituximab, and tocilizumab, etc. 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 or non-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(ln is excluded); 8. 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; 9. subjects with psychiatric disorders and severe cognitive impairments; 10. subjects who have participated in other clinical trials within the past 3 months prior to enrollment; 11. subjects who have received immunosuppressive agents or biologics with therapeutic effects for indications within 5 half-life prior to enrollment; 12. pregnant women or women planning to conceive; 13. subjects whom the investigator believes have other reasons that make them unsuitable for inclusion in this study.