Safety and Efficacy of Universal CAR-T Cells (UWD-CD19) Combined with Immunosuppressants in the Treatment of Refractory Autoimmune Diseases

Обзор

Autoimmune diseases refer to a common category of diseases caused by the immune system reacting to self-antigens, leading to tissue damage. Autoimmune diseases encompass a wide variety of conditions, such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, inflammatory myopathies, ANCA-associated vasculitis. Current treatments for autoimmune diseases include glucocorticoid, immunosuppressants, and biologics. B cell-driven humoral immune abnormalities are a central pathogenic mechanism in many autoimmune diseases. When autoreactive B cells are excessively activated, they produce large amounts of autoantibodies and immune complexes. These antibodies and immune complexes can cause damage to various tissues and organs, leading to the development of multiple autoimmune diseases. Therefore, targeting B cells to treat autoimmune diseases is an attractive therapeutic strategy. Clinical studies are exploring the use of CD19-targeting CAR-T cells for the treatment of autoimmune diseases, and their therapeutic efficacy has been demonstrated. In this study, we investigate the safety and efficacy of universal CD19-targeting CAR T cells in the treatment of autoimmune diseases.

Вмешательства

• Биопрепарат anti-CD19 CAR-T cells
  UWD-CD19

Первичные конечные точки

• Evaluate the safety of UWD-CD19 cell injection in the treatment of refractory autoimmune diseases. [Срок оценки: 0-6 months]
• Maximum tolerated dose of UWD-CD19 cells [Срок оценки: 28 days]

Вторичные конечные точки (12)

• Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2000) score [Срок оценки: 90 days, 180 days, 360 days]
• Low Lupus Disease Activity State(LLDAS) [Срок оценки: 90 days, 180 days, 360 days]
• Systemic Sclerosis Combined Response Index (CRISS) response [Срок оценки: 90 days, 180 days, 360 days]
• Modified Rodnan Skin Score (mRSS) [Срок оценки: 90 days, 180 days, 360 days]
• Vasculitis disease activity assessment (BVAS score) [Срок оценки: 90 days, 180 days, 360 days]
• EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) [Срок оценки: 90 days, 180 days, 360 days]
• PhGA in patients with inflammatory myopathies [Срок оценки: 90 days, 180 days, 360 days]
• PtGA in patients with inflammatory myopathies [Срок оценки: 90 days, 180 days, 360 days]
• HAQ score in patients with inflammatory myopathies [Срок оценки: 90 days, 180 days, 360 days]
• Extramuscular disease activity score [Срок оценки: 90 days, 180 days, 360 days]
• Muscle enzyme levels [Срок оценки: 90 days, 180 days, 360 days]
• PK parameters-Cmax [Срок оценки: 0-3 months]

Критерии участия

Критерии включения

• Age between 18-80 years (inclusive), male or female.
• >40kg.
• 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.
• 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.
• 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.
• Willing to participate in the trial and sign the informed consent form.

Disease-Specific Inclusion Criteria:

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.

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.

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.

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.

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.

Критерии исключения

• Subjects with a history of alcohol abuse or substance abuse within the past 24 weeks;
• Subjects with other psychiatric disorders such as schizophrenia or major depressive disorder;
• Subjects with a history of malignancies other than B-cell lymphoma;
• Subjects with overlapping diseases that affect the assessment of disease activity;
• Subjects with infections such as human immunodeficiency virus (HIV), hypogammaglobulinemia, T-cell deficiency virus infection, or chronic hepatitis B or C;
• Subjects with known active tuberculosis (TB) infection or bacterial infections;
• Subjects with a history of myocardial infarction, cardiac angioplasty or stent placement, unstable angina, active arrhythmia, or other clinically significant heart diseases within 6 months prior to screening;
• Subjects with a history of symptomatic deep vein thrombosis or pulmonary embolism within 6 months prior to screening;
• Subjects with alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels ≥3×ULN, or bilirubin >1.5×ULN, excluding abnormalities caused by theautoimmune disease;
• Subjects with chronic kidney failure stage 4 or above, defined as an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² or serum creatinine >2.5 mg/dL;
• At the screening visit, subjects with any of the following significant hematologic abnormalities caused by bone marrow suppression, excluding abnormalities due to the autoimmune disease:

• Hemoglobin <70 g/L;
• Absolute neutrophil count <500/mm³;
• Platelet count <50,000/mm³;
• Subjects with a history of severe adverse reactions to cyclophosphamide or fludarabine;
• Subjects with a prior history of CAR-T therapy;
• Subjects who received live vaccines within 30 days prior to CAR-T cell infusion;
• Subjects deemed unsuitable for participation in the study by the investigator.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT06821659 · M20250037

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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