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

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:

3. 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 treatmentwithin 2 weeks before examination); c. Hemoglobin ≥60g/L;

4. 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 diseaseitself);

5. Renal function: creatinine clearance rate (CrCl) ≥ 60 ml/minute(Cockcroft/Faultformula);

6. Coagulation function: International standardized ratio (INR) < 1.5 x ULN,prothrombintime(PT) < 1.5 x ULN;

7. Cardiac function: Good hemodynamic stability. 3. Female subjects of childbearingpotential and male subjects whose partner is a female of childbearing potential arerequired to use medically approved contraception or abstain from sex for at least 6months 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 participatein this clinical study, sign an informed consent form, have good compliance, andcooperate with follow-up.

Inclusion Criteria for Relapsing refractory dry syndrome:

1. Meets 2002 AECG criteria or 2016 ACR/EULAR classification criteria for primary drysyndrome (pSS);

2. Definition of disease activity: investigator-assessed disease ESSDAI score of 5 orhigher;

3. Definition of relapsed and refractory disease: ineffective conventional treatment orrelapse of disease activity after remission. Definition of routine treatment: Use ofglucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of thefollowing 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 ofground-glass exudates on chest HRCT and FVC or DLCO <70% predictive value onpulmonary function tests;

3. IDefinition of relapsed and refractory disease: ineffective conventional treatmentor relapse of disease activity after remission. Definition of routine treatment: useof 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;

4. Definition of progressiveness; 1) Definition of cutaneous progression: increase inmRSS >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 leasttwo abnormalities are found in the following five core measurements (PhGA, PtGA, orextramuscular disease activity score ≥ 2 points; total HAQ score ≥ 0.25; muscleenzyme 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) andcyclophosphamide, as well as any of the following immunomodulatory drugs for morethan 6 months: antimalarials, methotrexate, leflunomide, cyclophosphamide,azathioprine, mertiomate, tacrolimus, cyclosporine, and biologics, includingrituximab, belimumab and tetracycline.

Inclusion criteria for relapsing refractory rheumatoid arthritis:

1. Meets the diagnostic criteria of the 2010 ACR/EULAR classification. Diagnosis ofmoderately or severely active rheumatoid arthritis with a previous diagnosis ofrheumatoid 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/hduring the Screening Period;

4. EULAR definition of refractory rheumatoid arthritis:

5. Failure of treatment according to EULAR recommended guidelines and failure oftreatment with ≥2 b/tsDMARDs despite failure of treatment with csDMARDs. (i) unlesstreatment with bDMARDs/tsDMARDs is limited due to socioeconomic factors; and (ii) iftreatment with csDMARDs is contraindicated, then failure of treatment with ≥2b/tsDMARDs of different mechanisms also fulfills the condition);

6. Symptom management of RA is considered problematic by both the patient and thephysician;

7. Signs suggestive of active or progressive disease if at least 1 of the following 5items is met

8. At least moderate disease activity (DAS28-ESR >3.2 or CDAI >10);

9. Signs and/or symptoms suggestive of active disease;

10. Inability to reduce glucocorticoids to less than 7.5 mg/day prednisone orequivalent;

11. Rapid imaging progression (1-year increase of ≥5 points in van der Heijdemodified Sharp score);

12. Decreased quality of life due to RA, although RA is well controlled;

13. Refractory rheumatoid arthritis is diagnosed if three of the above criteria aremet.

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. Subjects with active or suspected fungal, bacterial, viral, or other infections that are uncontrolled or require treatment; 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. SSubjects 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; subjects with positive hepatitis C virus (HCV) antibodies and positive peripheral blood HCV RNA; subjects with positive human immunodeficiency virus (HIV) antibodies; subjects with positive for syphili; 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;
2. 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 othermyeloproliferative 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.