Allogeneic CD19/BCMA-Targeted CAR-γδT Cell Therapy: Safety and Preliminary Pharmacodynamics in Relapsed/Refractory Autoimmune Diseases

Официальное название

Safety and Preliminary Pharmacodynamics of Allogeneic CD19/BCMA-Targeted CAR-γδT Cell Therapy in Patients With Relapsed/Refractory Autoimmune Diseases

Обзор

This study is a single-arm, intervention, dose-escalation clinical trial to evaluate the safety of allogeneic CD19/BCMA-targeted CAR-γδT cell in the treatment of relapsed/refractory autoimmune diseases

Вмешательства

• Биопрепарат Allogeneic CD19/BCMA-targeted CAR-γδT cell injection
  Biological: Allogeneic CD19/BCMA-targeted CAR-γδT cell. Following lymphodepletion with chemotherapy (cyclophosphamide and fludarabine), patients will be treated with dose-escalation phase (3+3 design): Dose A (5 × 10\^6 CAR+cells) ,Dose B(1 × 10\^7 CAR+cells), Dose C (1.5 × 10\^7 CAR+cells).
• Препарат Cyclophosphamide
  Eligible subjects will undergo lymphodepletion chemotherapy 5 to 3 days prior to cell infusion. The recommended lymphodepletion regimen comprises cyclophosphamide (300 mg/m² administered 3 days).
• Препарат Fludarabine
  Eligible subjects will undergo lymphodepletion chemotherapy 5 to 3 days prior to cell infusion. The recommended lymphodepletion regimen comprises fludarabine (30 mg/m² administered 3 days).

Первичные конечные точки

• Adverse Event [Срок оценки: 6 months]
• Incidence of Dose-Limiting Toxicities (DLTs) [Срок оценки: First infusion date of allogeneic CD19/BCMA-targeted CAR-γδT cell to 28 days end cell infusion]

Вторичные конечные точки (3)

• PK(Pharmacokinetics):Number and Copy Number of CD19/BCMA-targeted CAR-γδT cells [Срок оценки: 12 months]
• PK(Pharmacokinetics): Persistence of CD19/BCMA-targeted CAR-γδT cells [Срок оценки: 12 months]
• PD(Pharmacodynamics)：Peak Level of Cytokines in Serum [Срок оценки: 12 months]

Критерии участия

Критерии включения

• Age ≥18 years (including 18 years), no gender restrictions.
• Confirmed by flow cytometry to express CD19 or BCMA antigen on the surface of peripheral blood B cells.
• Major organ function must meet the following requirements (excluding abnormalities related to active autoimmune disease):
• Bone marrow function: Neutrophil count ≥ 1 × 10\^9/L (no colony-stimulating factor therapy within 2 weeks prior to testing); Haemoglobin ≥ 60 g/L.
• Liver function: Alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal (ULN) (excluding ALT elevation due to inflammatory myopathy) ; Aspartate Aminotransferase (AST) ≤ 3 times the upper limit of normal (ULN) (excluding AST elevation due to inflammatory myopathy); Total Bilirubin (TBIL) ≤ 2 times ULN (may be relaxed to ≤ 3.0 times ULN for subjects with Gilbert's syndrome).
• Renal function: Creatinine clearance (CrCl) ≥ 30 ml/min (calculated using the Cockcroft-Gault formula, excluding acute CrCl decline due to target disease; lupus nephritis (LN) patients excluded).
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.
• Female subjects of childbearing potential and male subjects with partners of childbearing potential must use medically approved contraception or abstain from sexual intercourse for at least 6 months during study treatment and for at least 6 months after study treatment completion.
• Voluntary participation in this clinical study, signing of informed consent, good compliance, and ability to complete follow-up.

Disease-specific inclusion criteria:

• Relapsed/refractory systemic lupus erythematosus
• Diagnosis of systemic lupus erythematosus (SLE) meeting the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria.
• Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2000) ≥ 8 points; or significant organ involvement, such as lupus nephritis (histologically confirmed active nephritis of type III or IV, with or without type V involvement; National Institutes of Health \[NIH\] activity score > 2 points; evidence of elevated chronicity index; urine protein/creatinine ratio > 1.0 g/g, or 24-hour urine protein quantification > 1.0 g).
• Refractory or recurrent disease is defined as: no response after more than 6 months of conventional therapy, or recurrence of disease activity following remission. Conventional therapy is defined as: glucocorticoids combined with one or more of the following immunomodulatory agents: cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics such as rituximab, belimumab, or tatalimab.
• Refractory/Recurrent/Progressive Systemic Sclerosis
• Scleroderma diagnosis conforms to the 2013 ACR（American College of Rheumatology） classification criteria.
• Positive for scleroderma-associated antibodies.
• Presence of diffuse cutaneous sclerosis or active interstitial lung disease (high-resolution computed tomography (HRCT) showing ground-glass opacities).
• Definition of recurrent/refractory: No response to conventional therapy for over 6 months, or recurrence following remission. Conventional therapy defined as: Glucocorticoids combined with any one or more of the following immunomodulators: cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics such as belimumab, rituximab, or tocilizumab.
• Progressive definition: Rapid progression of cutaneous lesions (Modified Rodnan Skin Score (mRSS) increase > 25%); or progression of pulmonary lesions (Forced Vital Capacity (FVC) decline ≥10%, or FVC decline ≥5% accompanied by Diffusion Capacity for Carbon Monoxide (DLCO) decline ≥15%).

Note: Fulfilment of either criterion 4 or 5 is sufficient.

• Refractory/Recurrent/Progressive Inflammatory Myopathies
• Diagnosis of inflammatory myopathy conforms to the 2017 EULAR（European Alliance of Associations for Rheumatology）/ACR classification criteria (including dermatomyositis (DM), polymyositis (PM), anti-synthetase syndrome (ASS), and necrotising myopathy (NM)).
• Muscle involvement present, Manual Muscle Test - 8 (MMT-8) score < 142 points, and at least 2 abnormalities in the following 5 core indicators: Physician Global Assessment (PhGA), Patient Global Assessment (PtGA) or extra-muscular disease activity score ≥ 2 points; Health Assessment Questionnaire (HAQ) total score ≥ 0.25 points; Muscle enzyme levels ≥1.5 times the upper limit of normal.
• Definition of recurrent/refractory: No response to conventional therapy for over 6 months, or relapse following remission. Conventional therapy defined as: Glucocorticoids combined with any one or more of the following immunomodulators: cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics such as belimumab, rituximab, or tocilizumab.
• Definition of progressive disease: Rapid progression of interstitial lung disease within a short timeframe.

Note: Meeting any one criterion from either section 4 or 5 suffices.

• Refractory/Recurrent Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis
• Diagnosis of ANCA-associated vasculitis conforms to the 2022 ACR/EULAR criteria, encompassing microscopic polyangiitis, granulomatous polyangiitis, and eosinophilic granulomatous polyangiitis.
• ANCA-associated antibody testing is positive (myeloperoxidase antibody \[MPO-ANCA\] or proteinase 3 antibody \[PR3-ANCA\] positive).
• Birmingham Vasculitis Activity Score (BVAS) ≥15 points (out of 63 total points), indicating active vasculitis.
• Refractory/recurrent definition: Failure to respond to conventional therapy for over 6 months, or recurrence following remission. Conventional therapy is defined as:Use of glucocorticoids in combination with any one or more of the following immunomodulatory agents: cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics such as belimumab, rituximab, or tocilizumab.
• Refractory/Recurrent Connective Tissue Disease-Associated Thrombocytopenia
• Diagnosis of connective tissue disease conforming to the latest classification criteria, including but not limited to systemic lupus erythematosus, primary Sjögren's syndrome, antiphospholipid syndrome, and undifferentiated connective tissue disease.
• Diagnosed with connective tissue disease-associated thrombocytopenia, with platelet count < 30 × 10⁹/L, or platelet count < 50 × 10⁹/L accompanied by bleeding tendency.
• Bone marrow morphology consistent with features of immune thrombocytopenia.
• Previous treatment with at least one course of glucocorticoid pulse therapy, or high-dose glucocorticoids combined with one or more immunosuppressants (including biologics) for at least three months, failing to achieve partial remission or unable to maintain efficacy during glucocorticoid tapering.

Критерии исключения

• -Individuals with a history of severe drug allergies or an allergic constitution.
• Presence or suspected presence of uncontrolled or treatable fungal, bacterial, viral, or other infections.
• Active, severe central nervous system disorders caused by autoimmune or non-autoimmune diseases (including epilepsy, psychosis, organic brain syndrome, cerebrovascular accident, encephalitis, central nervous system vasculitis).
• Patients with cardiac insufficiency.
• Patients with congenital immunoglobulin deficiency.
• History of malignant tumours within the past five years.
• End-stage renal disease (excluding lupus nephritis (LN) patients).
• Hepatitis B surface antigen (HBsAg) positive or hepatitis B core antibody (HBcAb) positive with peripheral blood hepatitis B virus (HBV) DNA > upper limit of normal; hepatitis C virus (HCV) antibody positive with peripheral blood hepatitis C virus (HCV) RNA positive; human immunodeficiency virus (HIV) antibody positive; positive syphilis test.
• Individuals with psychiatric disorders or severe cognitive impairment.
• Participants who have been enrolled in another clinical trial within the three months preceding study entry.
• Individuals who have received immunosuppressive agents or biological agents for therapeutic indications within five half-lives prior to study entry.
• Pregnant women or women planning pregnancy.
• Individuals deemed by the investigator to have other conditions rendering them unsuitable for inclusion in this study.

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: NCT07490275 · IIT2026017

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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