Clinical Study Evaluating the Safety and Efficacy of IC19 CAR-T Cell Therapy for Refractory Systemic Lupus Erythematosus

This study is an open label, single arm exploratory clinical trial of IC19 CAR-T cell therapy for refractory systemic lupus erythematosus. Patients who are still in an active state after systemic treatment using the standard treatment regimen specified in the treatment guidelines were selected to receive IC19 CAR-T cell single pulse infusion therapy.

1. The "3+3" dose escalation method will be adopted, with 1 × 10 \^ 8 CAR-T cells/dose and 2 × 10 \^ 8 CAR-T cells/dose, and two dose groups increasing sequentially. Due to the specificity of cell preparations, it is allowed for the actual dosage of each dose group to fluctuate by ± 30%.
2. Three subjects are enrolled in each dose group first, and within the same dose group, the cell transfusion interval between the first two subjects should not be less than 14 days. If no dose limiting toxicity (DLT) is observed in a certain dose group, the dose will be increased to the next dose; If one case of DLT occurs, this dose group needs to be divided into three additional subjects (a total of six subjects). If no new DLT occurs, the dosage will be increased to the next dose; If more than 1/6 of the 6 subjects develop DLT, the dose escalation will be terminated, and the Safety Review Committee (SRC) will discuss whether to reduce the dose and continue the monotherapy study.
3. Definition of DLT: Any of the following events related to the investigational drug (definitely related, likely related, possibly related) that occur within 28 days after a subject receives any IC19 CAR-T cell infusion:

1) Any grade 4 or 5 adverse events related to IC19 CAR-T cells that occur after treatment, excluding laboratory test indicators of no clinical significance; 2) Any grade 3 adverse events related to IC19 CAR-T cells that occur after treatment and do not improve to ≤ grade 2 within 7 days, excluding clinically insignificant laboratory test indicators; 3) Any grade 3 epileptic seizures that occur after treatment and cannot be relieved to ≤ grade 2 within 3 days;

The following expected events will not be considered DLT:

Hematology:

1. Grade 3 neutropenia or Grade 4 neutropenia lasting no more than 28 days;
2. Grade 3 or 4 leukopenia;
3. Grade 3 or 4 lymphocyte reduction;
4. Grade 3 anemia or Grade 4 anemia lasting no more than 28 days;
5. Grade 3 thrombocytopenia or Grade 4 thrombocytopenia lasting no more than 28 days;
6. Other types of blood cell reduction besides those mentioned above.

Non hematology:

1. Grade 3 transaminase and bilirubin elevation should be restored to ≤ Grade 2 within 2 weeks;
2. Grade 3 hemophagocytic syndrome recovers to ≤ Grade 2 within 2 weeks;
3. Grade 3 chills, recover to ≤ Grade 2 within ≤ 72 hours;
4. Grade 3 hypotension (without other CRS symptoms), requiring vasopressor support and recovering to ≤ Grade 2 within ≤ 72 hours;
5. Level 3 CRS, recover to ≤ Level 2 within ≤ 72 hours;
6. Grade 3 ICANS ≤ 7 days, with remission to ≤ Grade 2 within 1 week and remission to baseline within ≤ 28 days.

For grade 3 or 4 toxicity that occurs after 28 days of IC19 CAR-T cell transfusion, SRC will discuss the specific situation. In this study, except for CRS and ICANS, which will be classified according to the ASTCT 2019 consensus grading criteria, adverse events of subjects will be classified according to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE 5.0).

Eligibility Criteria:
Inclusion Criteria:

1. Subjects diagnosed with systemic lupus erythematosus who meet the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for SLE;
2. Prior to screening, treatment with glucocorticoids (sufficient or shock therapy) combined with immunosuppressants (cyclophosphamide, mycophenolate mofetil, antimalarial drugs, azathioprine, methotrexate, leflunomide, tacrolimus, cyclosporine, etc.) and at least one biological agent (rituximab, belimumab, tacrolizumab, etc.) must have been received for at least 2 months, and the dosage must be stable for more than 2 weeks. The disease should still be active or recur after disease remission.

Oral corticosteroids need to meet the following conditions:

1. Prednisone (or equivalent) ≥ 7.5 mg/day and ≤ 60 mg/day;
2. When used in combination with immunosuppressants and/or biologics, there is no minimum daily dose requirement for glucocorticoids.

3. When screening, the disease activity score (SLEDAI-2000) should be ≥ 8 points; 4. During the screening period, it meets the criteria of being positive for anti nuclear antibodies (ANAs), anti dsDNA antibodies, or anti Smith antibodies.

5. Age range of 18-70 years old (including threshold), gender not limited; 6. Expected survival period of more than 3 months; 7. The functions of important organs meet the following requirements:

1. The bone marrow function needs to meet the following requirements: a. Neutrophil count ≥ 1 × 109/L; b. Platelets ≥ 50 × 109/L; c. Hemoglobin ≥ 60g/L;
2. Liver function: ALT ≤ 2.5 × ULN (upper limit of normal, ULN), AST ≤ 2.5 × ULN; TBIL ≤ 1.5 × ULN (for subjects with Gilbert syndrome, ALT and AST ≤ 5 × ULN, total bilirubin ≤ 3.0 × ULN);
3. Renal function: creatinine ≤ 1.5 × ULN or creatinine clearance rate (CrCl) ≥ 40 ml/min (Cockcroft/Gault formula);
4. Coagulation function: International normalized ratio (INR) ≤ 1.5 × ULN, prothrombin time (PT) ≤ 1.5 × ULN;
5. Cardiac function: Good hemodynamic stability, left ventricular ejection fraction (LVEF) ≥ 50%;
6. Finger pulse oxygen saturation ≥ 92% in non oxygen state; 8. Women of childbearing age who have a negative blood pregnancy test before the start of the trial and agree to participate in the trial until the last time Visit individuals who have adopted effective contraceptive measures; Male participants with reproductive partners agree to take effective contraceptive measures during the trial period until the last follow-up; And not in the lactation period.

9. The individual or legal guardian agrees to participate in this experiment and signs the informed consent form.

Exclusion Criteria:

1. Diseases of the central nervous system that have clinical significance in the past or during screening, such as seizures, epilepsy, epileptic seizures, cerebrovascular disease (ischemia/hemorrhage), cerebral edema, reversible posterior white matter encephalopathy, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, encephalitis, CNS vasculitis, or psychiatric disorders;
2. Screening for acute severe lupus nephritis within the first 2 months, defined as significant deterioration of kidney disease (such as the presence of urine sediment and other laboratory abnormalities) that the researcher believes may require the use of contraindicated drugs or high-dose corticosteroids (prednisone ≥ 100 mg/d or equivalent corticosteroid treatment ≥ 14 days) for treatment in the first 2 months of the study.
3. If there is an uncontrolled lupus crisis within the first 2 months of screening, the researcher has assessed that it is not suitable to participate in this study;
4. A large amount of serous fluid accumulation (such as pleural effusion and peritoneal effusion) with compression symptoms that cannot be controlled after treatment;
5. Other active autoimmune diseases (such as Crohn's disease and rheumatoid arthritis) that require systemic immunosuppressive therapy within the first 2 years of screening, except for SLE;
6. Patients who have received or are waiting for hematopoietic stem cell/bone marrow transplantation or organ transplantation in the past;
7. Individuals who have previously received gene modified cell therapy, such as TCR-T therapy, CAR-T therapy, etc;
8. Screening for clinical study drugs used for any other autoimmune diseases within the first 3 months. But if the research treatment is ineffective or if the disease progresses, and at least 5 half lives have passed before screening, it is allowed to be included in the group;
9. Have a history of ≥ grade 2 bleeding within 30 days prior to screening, or require long-term continuous use of anticoagulant drugs (such as warfarin, low molecular weight heparin, or Xa factor inhibitors) for treatment;
10. Vaccination with live or attenuated vaccines within 6 weeks prior to screening;
11. Active hepatitis B or hepatitis C virus is defined as: subjects who are positive for hepatitis B B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and whose peripheral blood HBV-DNA detection is higher than the lower limit of detection (HBsAg positive but whose peripheral blood HBV-DNA detection is lower than the lower limit of detection according to the Guidelines for the Prevention and Treatment of Chronic Hepatitis B, Version 2022, at least 4 weeks of antiviral treatment shall be carried out before the first use of the study drug, and antiviral treatment shall be continued for 6-12 months during the study process, and the levels of HBV-DNA, HBsAg and ALT shall be monitored every 1-3 months); Hepatitis C virus (HCV) antibody positive and peripheral blood HCV-RNA detection above the detection limit; HIV antibody positive; Positive syphilis antibody;
12. Active EB virus and cytomegalovirus, defined as: subjects with positive or negative IgM antibodies in EB virus serum but EBV-DNA higher than normal values; Subjects with IgM antibody positive or IgM antibody negative but CMV-DNA higher than normal in the serum of cytomegalovirus (CMV);
13. Within the past year, there have been severe chronic obstructive pulmonary disease, interstitial lung disease, severe asthma, and clinically significant abnormalities in lung function tests, such as moderate to severe pulmonary arterial hypertension (average pulmonary arterial pressure detected by echocardiography\>60mmHg) that require oxygen storage mask oxygen therapy or non-invasive or invasive ventilator assisted breathing during screening; Interstitial lung disease related to autoimmune diseases must meet all inclusion criteria;
14. Hypertension with poor drug control (systolic blood pressure\>160mmHg and/or diastolic blood pressure\>90mmHg) or a history of any of the following cardiovascular diseases within 6 months prior to screening: long QTc syndrome or QTc interval\>480 ms; Complete left bundle branch block, grade II/III atrioventricular block; Severe and uncontrolled arrhythmias requiring medication treatment; History of chronic congestive heart failure and NYHA ≥ 3 (refer to Appendix 2) with a heart ejection fraction below 50% within the 6 months prior to screening; Heart valve disease with CTCAE ≥ 3 grade; Within the first 6 months of screening, there has been a history of myocardial infarction, cardiac angioplasty or stent implantation, unstable angina, severe pericardial disease, or other clinically significant heart diseases;
15. History of symptomatic deep vein thrombosis or pulmonary embolism within the past 6 months prior to the start of screening;
16. Other untreated malignant tumors within the past 5 years or simultaneously, excluding cervical cancer in situ, basal cell carcinoma of the skin, and ductal carcinoma in situ of the breast;
17. Infections (fungi, bacteria, viruses, or others) that require intravenous injection of antibiotics for control or are uncontrollable For simple urinary tract infections and bacterial pharyngitis, if the researchers evaluate that they can be controlled through treatment, they can be included in the study;
18. Individuals who are known to have allergic reactions, hypersensitivity reactions, intolerance, or contraindications to any ingredients of drugs that may be used in the study (including fludarabine, cyclophosphamide, tocilizumab, albumin), or who have previously experienced severe allergic reactions;
19. Have a history of alcohol or drug abuse in the past 24 weeks;
20. The researcher shall determine whether the subjects have any factors that affect compliance with the protocol, or are unwilling or unable to comply with the procedures required in the research protocol.