an exploratory clinical study of anti-cd19 car nk cell (kn5501) in the treatment of relapsed/refractory immune nephropathy

Conditions: Nephropathy

Summary: a single arm, open-label pilot study is designed to determine the safety and effectiveness of anti-cd19 car nk cell injection (kn5501) in patients with immune nephropathy. 36 patients are planned to be enrolled in the dose-escalation trial. the primary endpoints are dlt and teaes. the secondary endpoints are the overall response rates (orr) and disease control rate (dcr)


Eligibility criteria:
common inclusion criteria: 1. age: ≥ 18 years old and ≤ 70 years old, male or female; 2. positive cd19 expression in peripheral blood b cells as determined by flow cytometry; 3. the functions of important organs meet the following requirements: 1. bone marrow hematopoietic function: 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) 3. coagulation function: international standardized ratio (inr) ≤ 1.5 x uln, prothrombin time (pt) ≤1.5 x uln. 4. cardiac function: good hemodynamic stability, left ventricular ejection fraction (lvef) ≥55%. 4. 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; 5. voluntarily participate in this clinical study, sign an informed consent form, have good compliance, and cooperate with follow-up. criteria for recurrent/refractory primary membranous nephropathy 1. primary membranous nephropathy diagnosed pathologically by renal biopsy; 2. screening period 24-hour urine protein quantification ≥3.5 g; 3. individuals who have not achieved partial remission (pr) after more than 6 months of treatment with hormonal and/or cytotoxic drugs, immunosuppressive therapy, and/or biologics (including but not limited to anti-cd20 monoclonal antibody); or individuals who have relapsed again after achieving complete remission/partial remission (cr/pr) with treatment (24h urine protein quantification ≥3.5g); 4. glomerular filtration rate (egfr, ckd-epi formula) ≥45 ml/min/1.73m2 during the screening period. criteria for relapsed/refractory iga nephropathy 1. primary iga nephropathy pathologically confirmed by renal biopsy; 2. treated (acei/arb analogs) for at least 3 months; 3. treatment with hormonal and/or cytotoxic drugs, immunosuppressive therapy, and/or biologics (including, but not limited to anti-cd20 monoclonal antibody) for more than 6 months, 24-hour urine protein quantification ≥ 1.0 g; or rapid progression of renal function (≥ 50% decrease in egfr within 3 months); or relapse after treatment to achieve complete remission/partial remission (cr/pr) (24-hour urine protein quantification ≥ 1.0 g); 4. glomerular filtration rate (egfr, ckd-epi formula) ≥30 ml/min/1.73m2 during the screening period. criteria for relapsed/refractory anca-associated vasculitis 1. meets 2022 acr/eular diagnostic criteria for anca vasculitis, including microscopic polyangiitis, granulomatous polyangiitis, eosinophilic granulomatous polyangiitis; 2. positive anca related antibodies (mpo-anca or pr3-anca positive); 3. renal biopsy pathology consistent with renal damage in anca-associated vasculitis; 4. the birmingham vasculitis activity scale (bvas) is ≥ 15 points (a total score of 63 points), indicating the activity of the vasculitis condition; 5. bvas score includes at least 2 abnormalities in the renal program; 6. definition of relapse/refractory : ineffective conventional treatment or relapse of disease activity after remission. definition of routine treatment: use of glucocorticoids (more than 1 mg/kg/d) and cyclophosphamide for ≥3 months, and any of the following immunomodulatory drugs: antimalarial drugs, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biological agents such as rituximab and belimumab; 7. glomerular filtration rate (egfr, ckd-epi formula) ≥15 ml/min/1.73m2 during the screening period. common exclusion criteria: 1. individuals 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. individuals with central nervous system disorders caused by ads or not caused by ads (including epilepsy, psychiatric disorders, organic encephalopathy syndromes, cerebrovascular accidents, encephalitis, central nervous system vasculitis); 4. individuals with relatively serious heart diseases, such as angina pectoris, myocardial infarction, heart failure, and arrhythmia; 5. subjects with congenital immunoglobulin deficiency; 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 recurrent/refractory primary membranous nephropathy 1. secondary membranous nephropathy (e.g., hepatitis b, systemic lupus erythematosus, drug-associated, malignancy-associated, etc.), or in combination with other renal diseases confirmed by renal biopsy; 2. type 1 or type 2 diabetes. exclusion criteria for relapsed/refractory iga nephropathy 1. exclude secondary iga nephropathy, including but not limited to: anaphylactic purpura, ankylosing spondylitis, systemic lupus erythematosus, desiccation syndrome, viral hepatitis, cirrhosis of the liver, rheumatoid arthritis, and mixed connective tissue disease; or in combination with other renal diseases confirmed by renal biopsy; 2. crescentic nephritis (pathologic diagnosis of \>50% crescentic bodies), micrognathic nephropathy with iga deposition, and other specific types of pathologic or clinical renal disease. exclusion criteria for relapsed/refractory anca-associated vasculitis 1. estimated glomerular filtration rate (egfr) \<15 ml/min/1.73 m2; 2. if the patient has alveolar hemorrhage invasive lung ventilation is required, estimated to last longer than the screening period.