A Clinical Study of Dual-Target, Universal CAR-T Cell Therapy for Refractory Systemic Lupus Erythematosus

A Phase I/IIa Clinical Study to Evaluate Universal Allogeneic CAR-T Cells (QT-019B) Targeting CD19 and BCMA for the Treatment of Refractory Systemic Lupus Erythematosus

This study is a single-arm, open-label clinical study designed to evaluate the safety and tolerability of QT-019B in subjects with refractory SLE and to determine the RD. The study has two phases: dose escalation and dose expansion, with a planned enrollment of 18-24 subjects.

Inclusion Criteria:

• 1. Age ≥18 years and ≤65 years at screening, gender is not limited.
• 2. Subjects diagnosed with systemic lupus erythematosus according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) SLE classification criteria.
• 3. Meets the criteria for refractory SLE: a) Must have received adequate standard treatment prior to screening, including glucocorticoids, immunosuppressants, biologics. b) Refractory SLE is defined as a failure to respond, or a documented adverse event or intolerance to glucocorticoids combined with other immunosuppressive therapies. The patient should have had received treatment with courses of at least two different non glucocorticoid immunosuppressive therapies (not necessarily simultaneously), at least one of which is a B cell-depleting biological agent such as belimumab, rituximab (unless such drugs are deemed contraindicated by the investigator or such drugs are not readily available to the patient).
• 4. Positive serological test during the screening period, for at least one of the following autoantibodies: antinuclear antibodies (ANA) at a titer of ≥1:80, or anti dsDNA (above the ULN), or anti-Sm (above the ULN), or other disease related autoantibodies (abovethe ULN).
• 5. At screening: a) SLE with or without Lupus Nephritis with SLEDAI-2K≥6. b) Severe, refractory SLE-ITP which is characterized by platelet count < 30×109/L, or < 50×109/L accompanied by a bleeding tendency.
• 6. Important organ functions during the screening period must meet the following requirements (excluding abnormalities related to SLE): a) Bone marrow function must meet the following: a. Neutrophil count ≥0.5×109/L; b. Hemoglobin ≥ 60g/L. b) Liver function: Alanine aminotransferase (ALT) ≤ 2×ULN, Aspartate aminotransferase (AST) ≤ 2×ULN, Total bilirubin (TBil) ≤ 2×ULN. c) Renal function: Creatinine clearance (CrCl) ≥ 30 ml/min (Cockcroft/Gault formula).
• 7. Female subjects of childbearing potential and male subjects whose partners are women of childbearing potential must use medically approved contraceptive measures or abstain from sex during the study treatment period and for at least 12 months after the end of the study treatment; female subjects of childbearing potential must have a negative serum HCG test within 7 days prior to study enrollment and must not be breastfeeding.
• 8. Voluntarily participate in this clinical study, sign the informed consent form, have good compliance, and cooperate with follow-up.

Exclusion Criteria:

• 1. Presence or definite history of central nervous system disorders, such as seizures, epilepsy, cerebrovascular accident (ischemic/hemorrhagic), cerebral edema, paralysis, aphasia, severe brain injury, dementia, Parkinson's disease, cerebellar disease, encephalitis, central nervous system vasculitis, or mental illness. If epilepsy caused by lupus is stable without seizures for 1 year before screening, screening may be performed.
• 2. Need for hemodialysis or high-dose corticosteroid therapy (prednisone ≥1.5 mg/kg/day or equivalent corticosteroid therapy ≥14 days) within 2 months before screening.
• 3. A large amount of serous cavity effusion with compressive symptoms that cannot be controlled after treatment (such as pleural effusion, ascites).
• 4. In the two years prior to the screening, subjects with other active autoimmune diseases (such as Crohn's disease or rheumatoid arthritis), except for SLE and its related conditions (such as SLE-induced thrombocytopenic purpura or SLE-associated autoimmune hemolytic anemia), as well as autoimmune thyroid disease and secondary Sjögren's disease.
• 5. Hematopoietic dysfunction that does not fulfill the criteria for SLE and its related ITP as determined by a bone marrow aspirate and/or biopsy, or subjects who have received or are waiting for hematopoietic stem cell/bone marrow transplantation or organ transplantation.
• 6. Subjects who have previously received gene-modified cell therapy, such as TCR-T, CAR-T, CAR-NK cells, and others.
• 7. Subjects who have used any other investigational drug for SLE within 4 weeks prior to screening.
• 8. Subjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and peripheral blood HBV DNA titer above the upper limit of detection, subjects with positive hepatitis C virus (HCV) antibody and positive peripheral blood HCV RNA, subjects with positive human immunodeficiency virus (HIV) antibody, subjects with positive syphilis test.
• 9. Uncontrolled hypertension (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg) within one month prior to screening, or any other serious cardiovascular diseases that could present potentially significant risks for participation in the study. Any of the following cardiovascular disease history within 6 months prior to screening: QTc prolongation syndrome or QTc interval >480 ms, complete left bundle branch block, second/third degree atrioventricular block, severe uncontrolled arrhythmia requiring medication, history of chronic congestive heart failure within 6 months prior to screening, NYHA≥3, cardiac ejection fraction <45%, myocardial infarction, cardiac angioplasty or stent implantation, unstable angina, severe pericardial disease, or other clinically significant heart disease within 6 months prior to screening.
• 10. A documented history of symptomatic deep vein thrombosis or pulmonary embolism within six months prior to the screening, or the presence of clinically significant pleural effusion, or an oxygen saturation level below 92% while breathing ambient air.
• 11. History of treated or untreated malignancy of any organ system within 5 years prior to screening (excluding basal cell carcinoma of the skin, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, follicular or papillary thyroid cancer, and other tumors with good prognosis).
• 12. Participants with any active infection, and any infection requiring systemic antimicrobial therapy within the past 30 days.
• 13. Any additional factors that the investigator thinks could put the subjects at risk, affect their adherence to treatment, disrupt the study's execution, or influence the study results.