an exploratory clinical study of cd19 car nk cell injection for the treatment of relapsed/refractory autoimmune diseases

Conditions: Autoimmune Diseases

Summary: 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.


Eligibility criteria:
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.