Safety and Efficacy of ES-NK Cell Injection in the Treatment of Refractory Lupus Nephritis: an Early Clinical Study

An Early Clinical Study to Evaluate the Safety and Efficacy of ES-NK Cell Injection in the Treatment of Refractory Lupus Nephritis

This is a single-arm, open-label, dose-escalation clinical trial. The entire trial is preliminarily expected to enroll 5 to 9 subjects.

The initial plan is to explore three dose groups: 2.5×10⁷, 7.5×10⁷, and 2.5×10⁸ cells/kg, with 3 subjects in each group. During the trial, based on a comprehensive assessment by the Safety Review Committee (SRC), the dose, dosing frequency, or dosing interval may be adjusted or increased.

In the dose-escalation phase, for the same dose group, one subject will be enrolled first. After obtaining at least 4 weeks of safety data, and upon the investigator's assessment confirming that the safety and tolerability risks are controllable, the second and third subjects can be enrolled. If the efficacy and safety data of the first subject in a dose group, based on the investigator's comprehensive judgment, indicate a significantly insufficient pharmacological effect, the study may proceed directly to the next dose group.

Before proceeding to each subsequent dose group, the SRC must evaluate the safety and pharmacodynamic data from the previous dose group for at least 4 weeks. Enrollment for the next group can only begin after the SRC confirms that the safety and tolerability risks are controllable and that the next dose level remains appropriate. The dose escalation will be determined based on safety data, combined with pharmacodynamic and efficacy data.

1. Must be >=5 years old and <=35 years old at the time of informed consent;
2. Diagnosed with SLE, with a renal biopsy within the past 24 months (for relapsed patients, biopsy must be after relapse) showing proliferative lupus nephritis (Class III or IV), or proliferative lupus nephritis with Class V (III/IV + V), and still in a moderately to severely active state at screening;
3. Either newly diagnosed or have shown poor response to current standard treatment after relapse;
4. Positive for antinuclear antibodies (ANA), and positive for anti-dsDNA or anti-Sm antibodies;
5. SLEDAI-2K score >=8;
6. Urine protein/creatinine ratio (UPCR) >=1.0 g/g (for those under 18 years old, urine protein quantification >=1.0 g/24 h);
7. (if applicable) Males and females with reproductive potential must use a highly effective contraceptive method or abstain continuously from the screening period until at least 1 year after the last dose, and must not donate sperm or eggs;
8. The subject (if applicable) and their parents/guardians can understand the trial information, purpose, and risks as described in the informed consent form, and can authorize the use of the subject's health information, providing a signed and dated informed consent form;
9. The subject (if applicable) and their parents/guardians are willing to participate as information providers in the study, providing the subject's health status, cognition, and physical capabilities (including information for grading scales);
10. The subject (if applicable) and their parents/guardians (if applicable) are willing to participate as information providers in the study, providing the subject's health status, cognition, and physical capabilities (including information for grading scales).

Exclusion Criteria:

1. SLE patients in lupus crisis, manifested by rapidly progressive lupus nephritis, diffuse alveolar hemorrhage, thrombotic microangiopathy, neuropsychiatric lupus, diffuse alveolar hemorrhage, pericardial tamponade, lupus mesenteric vascularization inflammation, catastrophic antiphospholipid antibody syndrome;
2. Presence of uncontrolled active infection at the time of enrollment, or active viral infection of HBV, HCV or syphilis, etc., or positive HIV screening;
3. Uncontrolled diabetes or hypertension, which is judged by the investigator to be unsuitable for immediate enrollment;
4. Severe bone marrow dysfunction, severe hepatic cardiopulmonary dysfunction, or severe coagulation dysfunction;
5. History of malignancy within the previous 5 years, with the exception of completely resected non-melanoma skin cancer, non-metastatic prostate cancer, and completely cured carcinoma in situ that have been stable for at least 6 months
6. Those who are on renal dialysis or are expected to need dialysis during the trial;
7. Receiving other systemic immunosuppressants other than SLE treatment (topical preparations for skin diseases can be used);
8. Received B or T cell targeted therapy before screening, and the B or T cell level is still depleted;
9. Previous organ or hematopoietic cell transplantation, or expected transplantation during the trial;
10. Those who have received CAR-T cell therapy or gene therapy in the past;
11. Immunization (live vaccine) within the week;
12. eGFR<=45ml/min/m^2 at screening;
13. Abnormal laboratory test indicators, including AST>=3×upper limit of normal (ULN), ALT>=3×ULN, TBIL>=3×ULN, creatinine>220umol/L, ALT/AST>5 times normal value, bilirubin >34umol/L, neutrophil count <1×10^9/L, platelet count <50×10^9/L, hemoglobin <80g/L;
14. There are other significant laboratory abnormalities and the investigator believes that the investigation is not suitable for immediate investigational drugs;
15. Pregnant or lactating women;
16. Contraindications to fludarabine or cyclophosphamide;
17. Participated in other clinical studies of investigational drugs or devices within 3 months, or are still within 5 half-lives of clinical trial drugs;
18. Presence of other concomitant serious diseases, conditions, or treatments that are assessed by the investigator to pose an unacceptable risk to the subject, or interfere with the subject's study compliance, or interfere with the conduct of the trial, or interfere with the evaluation of efficacy and safety.