An Exploratory Clinical Study Evaluating the Safety and Efficacy of Infusing the Non-virally Prepared BCMA/CD19 Bispecific CAR-T Cell Injection in Patients With Partially Relapsed/Refractory Autoimmune Diseases.
An Exploratory Clinical Study Evaluating the Safety and Efficacy of Infusing the Non-virally Prepared BCMA/CD19 Bispecific CAR-T Cell Injection in Patients With Partially Relapsed/Refractory Autoimmune Diseases.
This study is a single-center, open-label, single-dose exploration clinical trial for treating patients with partially relapsed/refractory autoimmune diseases by infusing FIT-(BCMA+CD19)-CAR-T cells after pre-treatment with cleansing therapy.
In this study phase, a traditional "3+3" trial design is employed for dose escalation.
This study intends to include some patients with relapsed/refractory autoimmune diseases. The subjects will undergo single infusion of FIT-(BCMA+CD19)-CAR-T cells after undergoing screening, collection of peripheral blood mononuclear cells (PBMC), and pre-treatment with conditioning chemotherapy. Apart from the baseline period, the time points for evaluating the therapeutic efficacy of the subjects after treatment are the 1st、2nd、3rd、6th、9th and 12th month after infusion, until disease progression (PD), relapse, change of treatment regimen, death, intolerable toxicity, at the discretion of the investigator, or voluntary withdrawal by the patient (whichever occurs first).
Toxicity will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Safety of FIT-(BCMA+CD19)-CAR-T cell therapy will be evaluated through laboratory tests, 12-lead electrocardiograms, vital signs, physical examinations, etc. Blood samples will be collected from subjects to assess cellular pharmacokinetics and explore the effects of cellular drugs on ferritin, C-reactive protein, and related cytokines.
Inclusion Criteria:
Voluntary participation in the clinical study, with the subject or their legally authorized representative fully understanding and providing written informed consent (ICF) for this study, and willingness to comply with and complete all trial procedures.
Aged 18 to 70 years.
ECOG performance status ≤ 2.
Life expectancy of at least 12 weeks.
Adequate venous access for apheresis and no other contraindications to blood cell separation.
Laboratory parameters at screening must meet the following requirements, with no receipt of cell growth factors within 7 days (or 2 weeks for long-acting formulations) prior to the screening hematology assessment:
Absolute neutrophil count ≥ 1.0 × 10⁹/L. Hemoglobin ≥ 60 g/L (without red blood cell transfusion within 14 days). Platelet count ≥ 50 × 10⁹/L (thrombocytopenia due to autoimmune disease may be excluded at the investigator's discretion).
Absolute lymphocyte count (ALC) ≥ 0.5 × 10⁹/L. Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (acute elevations due to autoimmune disease may be excluded at the investigator's discretion).
Creatinine clearance (Cockcroft-Gault formula) ≥ 30 mL/min.
Cardiac ejection fraction ≥ 45%, no pericardial effusion (excluding minimal or physiological effusion) confirmed by echocardiography (ECHO), and no clinically significant findings on electrocardiogram (ECG).
Baseline oxygen saturation > 92% while breathing room air.
Female subjects of childbearing potential must have a negative serum or urine pregnancy test (women who have undergone surgical sterilization or have been postmenopausal for at least 2 years are not considered to be of childbearing potential).
Male and female subjects willing to practice contraception from the time of signing the ICF until 12 months after the last dose of study drug.
Exclusion Criteria:
Active central nervous system (CNS) disease, such as epilepsy, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
Presence or suspicion of fungal, bacterial (including but not limited to Mycobacterium tuberculosis), viral, or other infection that is uncontrolled or requires intravenous antifungal, antibacterial, or antiviral therapy; uncomplicated urinary tract infection and uncomplicated bacterial pharyngitis are permitted.
Hepatitis B (positive for hepatitis B surface antigen [HBsAg] with HBV DNA > 1000 copies/mL), hepatitis C (positive for hepatitis C antibody), syphilis infection (positive for antibody), or human immunodeficiency virus (HIV) infection.
Prior or concomitant medication:
Prior use of any CAR-T cell product or other genetically modified T-cell therapy.
History of CD19-targeted therapy. Receipt of live vaccine within 4 weeks before enrollment. Use of another investigational medicinal product within 30 days before screening.
Receipt of biologic macromolecular drugs (e.g., rituximab, belimumab, telitacicept, adalimumab, etanercept, etc.) that have therapeutic effects on the target indication within 4 weeks or 5 half-lives before enrollment.
Receipt of > 20 mg/day of prednisone or equivalent doses of other corticosteroids within 2 weeks before enrollment.
Receipt of conventional synthetic disease-modifying drugs (e.g., cyclophosphamide, methotrexate, leflunomide, sulfasalazine, etc.) that have therapeutic effects on the target indication within 2 weeks before enrollment.
History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months before enrollment.
History of genetic syndromes associated with bone marrow failure, such as Fanconi anemia, Kostmann syndrome, Schwachman-Diamond syndrome, etc.
History of lymphoproliferative disease or malignancy (except for basal cell carcinoma of the skin, in situ carcinoma of the breast/cervix, and other diseases that are disease-free and have not been treated within the past five years).
Women of childbearing potential who are pregnant or breastfeeding.
Any medical activity that may interfere with the evaluation of study safety or efficacy.
In the investigator's judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up, or to comply with the requirements for study participation.
Specific Inclusion/Exclusion Criteria
Relapsed/Refractory Systemic Lupus Erythematosus (SLE)
Meet the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for SLE.
Disease activity score (SLEDAI-2000) ≥ 6 and at least one British Isles Lupus Assessment Group (BILAG-2004) category A (severe manifestation) or two category B (moderate manifestation) organ scores, or both; OR SLEDAI-2000 ≥ 8.
Definition of relapsed/refractory: persistent disease activity despite conventional therapy for more than 6 months, or recurrence of disease activity after remission. Conventional therapy is defined as the use of corticosteroids and cyclophosphamide, plus any one or more of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including rituximab, belimumab, telitacicept, etc.
Relapsed/Refractory Sjögren's Syndrome
Meet the 2002 AECG criteria or the 2016 ACR/EULAR classification criteria for primary Sjögren's syndrome.
Disease activity score (ESSDAI) ≥ 6.
Positive anti-SSA/Ro antibody.
Definition of relapsed/refractory: persistent disease activity despite conventional therapy for more than 6 months, or recurrence of disease activity after remission. Conventional therapy is defined as the use of corticosteroids and cyclophosphamide, plus any one or more of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including rituximab, belimumab, telitacicept, etc.
Relapsed/Refractory/Progressive Diffuse Scleroderma
Meet the 2013 ACR classification criteria for scleroderma.
Positive scleroderma-associated antibodies.
Diffuse cutaneous sclerosis manifestations or active interstitial lung disease (ground-glass opacities on HRCT).
Definition of relapsed/refractory: persistent disease activity despite conventional therapy for more than 6 months, or recurrence of disease activity after remission. Conventional therapy is defined as the use of corticosteroids and cyclophosphamide, plus any one or more of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including rituximab, belimumab, telitacicept, etc.
Definition of progressive: rapid skin progression (increase in mRSS > 25%); or progression of lung disease (FVC reduction ≥ 10%, or FVC reduction > 5% accompanied by DLCO reduction ≥ 15%).
Note: Fulfillment of either criterion 4 or criterion 5 is sufficient.
Relapsed/Refractory/Progressive Inflammatory Myopathy
Meet the 2017 EULAR/ACR classification criteria for inflammatory myopathy (including DM, PM, ASS, and NM).
Positive myositis antibodies.
For patients with muscle involvement: MMT-8 score < 142 and at least two of the following five core set measures are abnormal (PhGA, PtGA, or extra-muscular disease activity score ≥ 2; total HAQ score ≥ 0.25; muscle enzyme levels ≥ 1.5 times the upper limit of normal); OR MMT-8 score ≥ 142 but with active interstitial lung disease (ground-glass opacities on HRCT).
Definition of relapsed/refractory: persistent disease activity despite conventional therapy for more than 6 months, or recurrence of disease activity after remission. Conventional therapy is defined as the use of corticosteroids and cyclophosphamide, plus any one or more of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including rituximab, belimumab, telitacicept, etc.
Definition of progressive: rapidly progressive interstitial pneumonia within a short period of time.
Note: Fulfillment of either criterion 4 or criterion 5 is sufficient.
Relapsed/Refractory ANCA-Associated Vasculitis
Meet the 2022 ACR/EULAR diagnostic criteria for ANCA-associated vasculitis, including microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis.
Positive ANCA-associated antibodies (MPO-ANCA or PR3-ANCA positive).
Birmingham Vasculitis Activity Score (BVAS) ≥ 15 (total score 63), indicating active vasculitis.
BVAS assessment must include at least one major item, at least three minor items, or at least two renal items (hematuria and proteinuria).
Definition of relapsed/refractory: persistent disease activity despite conventional therapy for more than 6 months, or recurrence of disease activity after remission. Conventional therapy is defined as the use of corticosteroids and cyclophosphamide, plus any one or more of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including rituximab, belimumab, telitacicept, etc.
Relapsed/Refractory/Catastrophic Antiphospholipid Syndrome
Meet the 2006 Sydney revised diagnostic criteria for primary antiphospholipid syndrome.
Positive medium-to-high titer antiphospholipid antibodies (IgG/IgM of LA, β2GP1, or aCL), with positivity detected more than twice within 12 weeks.
Definition of relapsed/refractory: recurrent thrombosis despite standard treatment with warfarin or alternative vitamin K antagonists (i.e., INR within therapeutic range) or standard therapeutic dose low molecular weight heparin (LMWH), and prior use of corticosteroids and cyclophosphamide.
Catastrophic antiphospholipid syndrome must meet all four of the following criteria: (1) involvement of three or more organs, systems, and/or tissues; (2) onset of symptoms within one week; (3) histological confirmation of small vessel occlusion in at least one organ or tissue; (4) positive aPL.
Note: Fulfillment of either criterion 3 or criterion 4 is sufficient.
Relapsed/Refractory Autoimmune Hemolytic Anemia
Meet the diagnostic criteria of the Chinese Guidelines for the Diagnosis and Treatment of Autoimmune Hemolytic Anemia in Adults (2023 Edition).
(i) Hemoglobin level meeting the criteria for anemia; (ii) decreased serum haptoglobin (< 250 mg/L), elevated total bilirubin (≥ 17.1 μmol/L, predominantly unconjugated bilirubin), elevated lactate dehydrogenase, and reticulocyte percentage > 4% or absolute reticulocyte count > 120 × 10⁹/L; (iii) detection of red blood cell autoantibodies.
Definition of relapsed/refractory: failure, intolerance, or contraindication to at least 3 months of therapy with corticosteroids in combination with at least one immunosuppressant (cyclophosphamide, azathioprine, vinca alkaloids, calcineurin inhibitors, mycophenolate mofetil) and/or rituximab (second-line therapy for patients with corticosteroid resistance, relapse, intolerance, dependence, or contraindications: rituximab), with persistent anemia and hemolytic symptoms of varying degrees, and laboratory findings not meeting partial remission criteria (HGB increase > 20 g/L, or HGB normalized but hemolytic biochemical parameters not fully normalized [including reticulocytes, haptoglobin, bilirubin, and lactate dehydrogenase], and transfusion-free for at least 7 days); OR achievement of complete remission (disappearance of clinical symptoms, normalization of red blood cell count, hemoglobin level, reticulocyte percentage, serum bilirubin level, and negative direct and indirect Coombs test) after the above therapy but relapse during maintenance therapy or after drug discontinuation.