Refractory / Relapsed Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis, Refractory / Relapsed Connective Tissue Disease-Associated Thrombocytopenia, Refractory / Relapsed / Progressive Systemic Sclerosis, Refractory/Relapsed Systemic Lupus Erythematosus, Refractory / Relapsing / Progressive Inflammatory Myopathy
Conditions
Keywords
CD19/BCMA, CAR-γδT, cell therapy
Brief summary
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
Interventions
BIOLOGICALAllogeneic 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).
DRUGCyclophosphamide
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).
DRUGFludarabine
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).
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* -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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Adverse Event | 6 months |
| Incidence of Dose-Limiting Toxicities (DLTs) | First infusion date of allogeneic CD19/BCMA-targeted CAR-γδT cell to 28 days end cell infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK(Pharmacokinetics):Number and Copy Number of CD19/BCMA-targeted CAR-γδT cells | 12 months | Number and copy number of CD19/BCMA-targeted CAR-γδT cells were assessed by number in peripheral blood. Blood samples were collected before and one year after cell infusion (until CD19/BCMA-targeted CAR-γδT cells were not detected for two consecutive times) to detect the number and copy number of CD19/BCMA-targeted CAR-γδT cells, and to evaluate the pharmacokinetics of CD19/BCMA-targeted CAR-γδT cells. |
| PK(Pharmacokinetics): Persistence of CD19/BCMA-targeted CAR-γδT cells | 12 months | Persistence of CD19/BCMA -targeted CAR-γδT cells assessed by number in peripheral blood. |
| PD(Pharmacodynamics)：Peak Level of Cytokines in Serum | 12 months | The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, interferon-γ（IFN-γ). Peak was defined as the maximum post-baseline level of the cytokine. |
Contacts
CONTACTYing Wang
Outcome results
None listed