Anti-CD19 Chimeric Antigen Receptor T Cells for Refractory Systemic Lupus Erythematosus

Inclusion criteria

• Male or female, aged 3-65 years.
• Have a diagnosis of SLE and meet the classification criteria of 2019 European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).
• Positive antinuclear antibody (ANA): ANA at a titer of ≥ 1:80 on Hep-2 cells or equivalent positive test (ever) and/or a positive anti-dsDNA serum antibody test (based on ELISA assay, ≥ 30 IU/mL).
• Refractory SLE and/or refractory lupus nephritis (LN):
• 4.1 Refractory SLE 4.1.1 Patients received at least 7.5 mg/kg/day of prednisolone to maintain low disease activity or the SLEDAI 2K score ≥8.
• Routine treatment is ineffective or the disease relapses after remission. Definition of routine treatment: use glucocorticoid (more than 1mg/kg/d) and cyclophosphamide for 6 months; and any of the following immunomodulatory drugs for more than 3 months: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biological agents such as rituximab, belizumab, or telitacicept;
• 4.2 Refractory LN 4.2.1 Diagnosis of SLE based on the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR), Biopsy-proven LN class III, IVa \[excluding III (C), IV-S (C) and IV-G (C)\] or, class V lupus nephritis combined with class III or IV, according to 2018 Revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) criteria, see Appendix 3. Biopsy must be performed within 6 months before or during screening.
• Refractory lupus nephritis is defined as no induced remission to treatment regimens containing at least one immunosuppressant (including glucocorticoids, CTX, tacrolimus, MME, and cyclosporine) after 3 to 6 months, accompanied by no reduction (or worsening) of proteinuria or persistent antibody positives.
• CD19+ on B cells and continuous withdrawal of the immunosuppressive drugs for more than 1 week.
• The blood routine lymphocyte count of the subjects is \> 1 × 109/L, and there is no cell collection contraindication.
• No severe allergy.
• Eastern Cooperative Oncology Group (ECOG) performance status score 0 to 2.
• Patients are expected to live for at least 90 days.
• Subjects and/or their guardian must understand and sign the informed consent.

Exclusion criteria

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Impaired consciousness or intracranial hypertension:
• Intracranial pressure elevation was above 15 mmHg;
• Organic encephalopathy syndrome, cerebrovascular accident, encephalitis or central nervous system vasculitis, visual impairment, and other brain lesions requiring intervention.
• Symptomatic congestive heart failure or severe cardiac arrhythmia:
• Previously documented left ventricular ejection fraction (LVEF) by echocardiography of \<45% in the 12 months;
• Abnormal electrocardiogram (ECG): left bundle branch block, bifascicular block or any clinically meaningful ECG abnormality;
• Congenital long QT syndrome or prolongation of the QT interval corrected for heart rate (QTcF) ≥ 470 ms. QTcF is calculated using Fridericia's Formula;
• Any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification;
• Unstable or poorly controlled angina pectoris, including the prinzmetal variant of angina pectoris;
• Myocardial infarction within 6 months.
• Manifestations of severe respiratory system failure:
• Hypoxemic respiratory failure: PaO2 \< 60 mmHg, PaCO2 \< 50 mmHg at sea level, resting and breathing air conditions;
• Subjects with pulmonary hypertension (PH): mean pulmonary artery pressure (mPAP) ≥25 mmHg measured by right heart catheterization (RHC);
• Subjects with hypercapnia (PaCO2 ≥ 50mmHg ) and/or ventilatory dysfunction (PH \<7.25 );
• Oxygen inhalation was required to maintain oxygen saturation;
• Acute or chronic respiratory diseases unrelated to SLE, such as acute pneumonia and interstitial lung disease.
• Co-existence with other malignancies.
• Disseminated intravascular coagulation (DIC).
• Sepsis or other uncontrollable infections: active uncontrolled systemic bacterial, viral, fungal, or parasitic infection (except for fungal nail infection) or other clinically significant active disease process.
• Uncontrollable diabetes: after at least 3 months of diet and exercise or similar treatment, fasting blood glucose (FBG) ≥ 8.0 mmol/L, postprandial blood glucose (PBG) ≥ 15 mmol/L, and glycosylated hemoglobin (HbA1c)≥8.0%; diabetic ketoacidosis or other uncontrollable complications of diabetes.
• Serious mental illness: alcohol or drug abuse, dementia, or any other condition that would impair the subject's ability to receive the planned treatment or to understand informed consent at the study site.
• Apparent and active intracranial lesions on cranial magnetic resonance imaging (MRI).
• Underwent organ transplantation, excepting SCT.
• Pregnant females or lactation.
• Positive test for infectious hepatitis, acquired immune deficiency syndrome (AIDS) or syphilis.
• No peripheral blood mononuclear cells (PBMC) collection or frozen PBMC for CAR T cell manufacturing.
• eGFR CKD-EPI \< 30 ml/min/1.73m2.
• Patients who are unable to discontinue immunosuppression agents for ≥7 days or whose condition recurs during discontinuation while the risk of serious adverse reactions is assessed by the investigator.
• Any active skin disease that may interfere with the evaluation of SLE, including but not limited to psoriasis, dermatomyositis, systemic sclerosis, non-SLE skin manifestations (e.g., cutaneous vasculopathies, peripapillary dilatation, fingertip sclerosis, rheumatoid nodules, erythema multiforme, leg ulcers), or drug-induced lupus.