An Exploratory Clinical Study of CD19 CAR NK Cell Injection for the Treatment of Relapsed/Refractory Autoimmune Diseases

Inclusion Criteria33

• Age: ≥ 18 years old and ≤ 65 years old, male or female;
• The functions of important organs meet the following requirements:
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• 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;
• 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);
• Renal function: creatinine clearance rate (CrCl) ≥ 60 ml/minute(Cockcroft/Fault formula);
• Coagulation function: International standardized ratio (INR) < 1.5 x ULN,prothrombin time(PT) < 1.5 x ULN;
• 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.
• Meets 2002 AECG criteria or 2016 ACR/EULAR classification criteria for primary dry syndrome (pSS);
• Definition of disease activity: investigator-assessed disease ESSDAI score of 5 or higher;
• Definition of relapsed and refractory disease: 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;
• Meets 2013 ACR classification criteria for systemic sclerosis;
• 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;
• IDefinition of relapsed and refractory disease: ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: use of glucocorticoids and one or more immunomodulatory drugs for more than 6 months, including antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine, and biologics including rituximab, belimumab, and tetanuscept;
• 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).
• Classification criteria for inflammatory myopathy in accordance with 2017 EULAR/ACR (including DM, PM, ASS, and NM);
• 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);
• Positive myositis antibodies;
• 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.
• 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;
• 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;
• C-reactive protein (CRP) ≥ 10 mg/L or erythrocyte sedimentation rate (ESR) ≥ 28 mm/h during the Screening Period;
• EULAR definition of refractory rheumatoid arthritis:
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• 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);
• Symptom management of RA is considered problematic by both the patient and the physician;
• Signs suggestive of active or progressive disease if at least 1 of the following 5 items is met
• At least moderate disease activity (DAS28-ESR >3.2 or CDAI >10);
• Signs and/or symptoms suggestive of active disease;
• Inability to reduce glucocorticoids to less than 7.5 mg/day prednisone or equivalent;
• Rapid imaging progression (1-year increase of ≥5 points in van der Heijde modified Sharp score);
• Decreased quality of life due to RA, although RA is well controlled;
• Refractory rheumatoid arthritis is diagnosed if three of the above criteria are met.