An Exploratory Clinical Study of the Safety and Efficacy of CD19 Chimeric Antigen Receptor NK Cell Injection for the Treatment of Relapsed/Refractory Autoimmune Diseases

CHEC2024-181

A single arm, open-label pilot study is designed to determine the safety and effectiveness of CD19 CAR NK cells in patients with autoimmune diseases. 36-72 patients are planned to be enrolled in the dose-escalation trial. The primary objective of the study was to evaluate the safety and feasibility of CD19 CAR-NK cells for the treatment of patients with autoimmune diseases. The secondary objective is to evaluate the efficacy of CD19 CAR-NK cells in patients with autoimmune diseases.

2024-06-30

2025-06-30

2026-06-30

Not yet recruiting

Early phase I

72

Common inclusion criteria: 1. Age: ≥ 18 years old and ≤ 65 years old, male or female; 2. The functions of important organs meet the following requirements: <!-- --> 1. Bone marrow hematopoietic function needs to meet: a. White blood cell count ≥ 3 x 10\^9/L b. Neutrophil count ≥ 1 x 10\^9/L (no colony-stimulating factor treatment within 2 weeks before examination); c. Hemoglobin ≥60g/L; 2. Liver function:ALT ≤ 3 x ULN,AST≤3 x ULN, TBIL≤1.5 x ULN(excluding Gilbert syndrome, total bilirubin ≤ 3.0 x ULN) (No requirements for conditions caused by the disease itself); 3. Renal function: creatinine clearance rate (CrCl) ≥ 60 ml/minute(Cockcroft/Fault formula); 4. Coagulation function: International standardized ratio (INR) \< 1.5 x ULN,prothrombin time(PT) \< 1.5 x ULN; 5. Cardiac function: Good hemodynamic stability. 3. Female subjects of childbearing potential and male subjects whose partner is a female of childbearing potential are required to use medically approved contraception or abstain from sex for at least 6 months during and at least 6 months after the end of the study treatment period; female subjects of childbearing potential have had a negative serum HCG test within 7 days prior to study enrollment and are not lactating; 4. Voluntarily participate in this clinical study, sign an informed consent form, have good compliance, and cooperate with follow-up. Inclusion Criteria for Relapsing refractory dry syndrome: 1. Meets 2002 AECG criteria or 2016 ACR/EULAR classification criteria for primary dry syndrome (pSS); 2. Definition of disease activity: investigator-assessed disease ESSDAI score of 5 or higher; 3. Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the following immunomodulatory drugs for more than 6 months: antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine, mertiomate, tacrolimus, cyclosporine, and biologics, including rituximab, belimumab and tetracycline; Inclusion criteria for Systemic Sclerosis: 1. Meets 2013 ACR classification criteria for systemic sclerosis; 2. If combined with interstitial pneumonia, interstitial changes suggestive of ground-glass exudates on chest HRCT and FVC or DLCO \<70% predictive value on pulmonary function tests; 3. Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the following immunomodulatory drugs for more than 6 months: antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine, mertiomate, tacrolimus, cyclosporine, and biologics, including rituximab, belimumab and tetracycline; 4. Definition of progressiveness; 1) Definition of cutaneous progression: increase in mRSS \>10%; 2) Definition of lung disease progression: 10% decrease in FVC or 5% decrease in FVC with 15% decrease in DLCO (OMERACT progression). Inclusion criteria for Recurrent refractory idiopathic inflammatory myopathy: 1. Classification criteria for inflammatory myopathy in accordance with 2017 EULAR/ACR (including DM, PM, ASS, and NM); 2. For those with muscle involvement, the MMT-8 score is lower than 142 and at least two abnormalities are found in the following five core measurements (PhGA, PtGA, or extramuscular disease activity score ≥ 2 points; total HAQ score ≥ 0.25; muscle enzyme levels are 1.5 times the upper limit of the normal range); 3. Positive myositis antibodies; 4. Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the following immunomodulatory drugs for more than 6 months: antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine, mertiomate, tacrolimus, cyclosporine, and biologics, including rituximab, belimumab and tetracycline. Inclusion criteria for relapsing refractory rheumatoid arthritis: 1. Meets the diagnostic criteria of the 2010 ACR/EULAR classification. Diagnosis of moderately or severely active rheumatoid arthritis with a previous diagnosis of rheumatoid arthritis ≥ 6 months; 2. A swollen joint count of ≥ 6 (based on 66 joint counts) and a tender joint count of ≥ 6 (based on 68 joint counts) during the Screening Period; 3. C-reactive protein (CRP) ≥ 10 mg/L or erythrocyte sedimentation rate (ESR) ≥ 28 mm/h during the Screening Period; 4. EULAR definition of refractory rheumatoid arthritis: <!-- --> 1. Failure of treatment according to EULAR recommended guidelines and failure of treatment with ≥2 b/tsDMARDs despite failure of treatment with csDMARDs. (i) unless treatment with bDMARDs/tsDMARDs is limited due to socioeconomic factors; and (ii) if treatment with csDMARDs is contraindicated, then failure of treatment with ≥2 b/tsDMARDs of different mechanisms also fulfills the condition); 2. Symptom management of RA is considered problematic by both the patient and the physician; 3. Signs suggestive of active or progressive disease if at least 1 of the following 5 items is met 1. At least moderate disease activity (DAS28-ESR \>3.2 or CDAI \>10); 2. Signs and/or symptoms suggestive of active disease; 3. Inability to reduce glucocorticoids to less than 7.5 mg/day prednisone or equivalent; 4. Rapid imaging progression (1-year increase of ≥5 points in van der Heijde modified Sharp score); 5. Decreased quality of life due to RA, although RA is well controlled; 6. Refractory rheumatoid arthritis is diagnosed if three of the above criteria are met. Common exclusion criteria: 1. Subjects with known severe allergic reactions, hypersensitivity, contraindication to any medications during the trial (cyclophosphamide, fludarabine, tozumabs), or subjects with a history of severe allergic reactions; 2. Existence or suspicion of uncontrollable or treatable fungal, bacterial, viral or other infections; 3. Subjects with central nervous system disorders due to autoimmune diseases or non-autoimmune diseases(including epilepsy, psychosis, organic encephalopathy syndromes, cerebrovascular accidents, encephalitis, central nervous system vasculitis); 4. Subjects with relatively serious heart diseases, such as angina pectoris, myocardial infarction, heart failure, and arrhythmia; 5. Subjects with congenital immunodeficiency diseases; 6. Subjects with malignant tumors (except for non-melanoma skin cancer and in situ cervical, bladder, and breast cancers that have been disease-free for more than 5 years); 7. Subjects with end-stage renal failure; 8. Subjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and HBV DNA titer in peripheral blood higher than the upper limit of detection; Patients with positive hepatitis C virus (HCV) antibodies and positive peripheral blood HCV RNA; People who are positive for human immunodeficiency virus (HIV) antibodies; Those who have tested positive for syphilis; 9. Subjects with mental illness and severe cognitive impairment; 10. Subjects who have received other clinical trial treatment within 3 months; 11. Pregnant or intending to conceive women; 12. In the opinion of the investigator, there are other reasons why subjects cannot be included in this study. Exclusion criteria for relapsing refractory dry syndrome: 1. Combined cirrhosis of the liver; 2. Combination of aplastic anemia (AA), myelodysplastic syndrome (MDS), or other myeloproliferative disease (MPD). Exclusion criteria for recurrent refractory idiopathic inflammatory myopathies: 1. Drug-induced myositis; 2. Inclusion body myositis; 3. Tumor-associated myositis (myositis occurring within 2 years of tumor diagnosis). Exclusion criteria for relapsed refractory rheumatoid arthritis: Functional status of rheumatoid arthritis graded at level 4 according to ACR.

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE1'], 'designInfo': {'allocation': 'NA', 'interventionModel': 'SINGLE_GROUP', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 72, 'type': 'ESTIMATED'}}

2024-06-18