Study of Therapeutic Efficacy of Anti-CD19 CAR-T Cells in Refractory Systemic Lupus Erythematosus

A Clinical Study on the Safety and Efficacy of Chimeric Antigen Receptor T Cell Injection Targeting CD19 Gene in the Treatment of Refractory Systemic Lupus Erythematosus

This is an investigator-initiated trial aimed at assessing the safety of anti-CD19 CAR-T cells in the treatment of refractory systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a serious autoimmune disease that can lead to extensive damage in multiple organs and systems, ultimately resulting in disability and even death. Children with SLE are particularly at risk of organ damage, especially to the kidneys, and tend to have a more severe and protracted course of the disease compared to adults.

Currently, the primary treatment for SLE relies on glucocorticoids and immunosuppressants to alleviate symptoms. However, due to the absence of a curative treatment, patients often require lifelong medication. In recent years, biological agents such as belimumab and rituximab have been introduced for the treatment of SLE, but these agents cannot completely eliminate autoimmune B cells in the bone marrow, leading to unsatisfactory overall outcomes. Furthermore, stopping the drugs can lead to relapse, and there is still no cure for SLE, leaving patients facing the challenges of lifelong medication and an incurable disease.

Since 2019, CAR-T cell therapy has been successfully applied to autoimmune diseases. Clinical studies have demonstrated that targeted CD19 CAR-T cells hold significant therapeutic potential for SLE. These cells effectively slow down the pathological progression of SLE and can also effectively treat severe cases. Furthermore, targeted CD19 CAR-T cells are also expected to restore the immune system in SLE patients, potentially allowing them to discontinue lifelong medication and avoid serious long-term side effects of drugs like hormones and immunosuppressants. The purpose of this study is to assess the safety and efficacy of the anti-CD19 CAR-T cells in the treatment of refractory SLE.

Inclusion Criteria

1. Age: ≥5 years old.

2. Refractory SLE Diagnosis:

   1. Diagnosed with SLE according to the 2019 EULAR/ACR classification criteria.
   2. Exhibit persistent moderate to severe disease activity (defined as a SLEDAI-2K score ≥ 8).
   3. Demonstrated failure or to achieve target disease control (LLDAS or remission) after a minimum of 6 months of standard-of-care therapy, including: high doses of glucocorticoids (≥1mg/kg/day prednisone or equivalent), hydroxychloroquine, and at least two DMARDs (including cyclophosphamide, MMF, azathioprine, methotrexate, cyclosporine, tacrolimus, sirolimus, leflunomide, tocilizumab, belimumab, and rituximab) for at least 6 months; or intolerant to conventional treatments.

   Note: Patients may also be eligible if they are documented as intolerant to these conventional treatments.

3. Disease Severity Validation: To ensure a "refractory" status, patients must satisfy at least one of the following:

   1. Active Major Organ Involvement (e.g., biopsy-proven Lupus Nephritis Class III, IV, or V; CNS lupus; or refractory hematological cytopenias).
   2. Steroid Dependence: Inability to taper glucocorticoid dose below 0.5 mg/kg/day (or equivalent) without a disease flare.

4. Organ Function:

   1. Cardiac: LVEF ≥ 55 %, with no significant clinical abnormalities on ECG.
   2. Renal: Estimated glomerular filtration rate (eGFR) 30 mL/min/1.73m2.
   3. Liver: AST and ALT ≤ 3.0 ULN, and total bilirubin ≤ 2.0 ULN.
   4. Pulmonary: No severe lung disease, with oxygen saturation (SpO2) ≥ 92% on room air.

5. Apheresis Suitability: Must meet institutional criteria for leukapheresis and have no contraindications to peripheral blood mononuclear cell (PBMC) collection.

6. Contraception: Females of childbearing age must have a negative urine pregnancy test at screening and agree to use effective contraceptive measures from enrollment until 1 year after MC-1-50 cell infusion.

7. Informed Consent: Voluntary written informed consent must be obtained from the subject (if applicable) and their lawful guardians prior to any screening procedures.

Exclusion Criteria:

1. Prior Cell Therapy: Previous treatment with any CAR-T cell therapy or other genetically modified effector cell products.

2. Neurological/CNS Involvement:

   1. Active central nervous system (CNS) lupus requiring clinical intervention within 60 days of screening (including seizures, delirium, or cerebrovascular events).
   2. Evidence of significant structural CNS damage on MRI or a history of severe seizures that may lower the threshold for ICANS.

3. Severe Renal Impairment and Fibrosis:

   1. Receiving renal replacement therapy (dialysis) within 3 months prior to infusion.
   2. Irreversible Renal Damage: Documented high chronicity on baseline biopsy (e.g., Chronicity Index >6/12) or extensive renal fibrosis, as these patients are unlikely to achieve functional recovery despite immunological remission.
   3. Significant nephropathy likely requiring high-dose glucocorticoids (≥1mg/kg/day prednisone or equivalent) or intensified DMARDs within 3 months of infusion.

4. Cardiac Conditions:

   Serious congenital heart disease; acute myocardial infarction within 6 months of screening; severe arrhythmias (e.g., multifocal premature ventricular tachycardia); large pericardial effusion; severe myocarditis; or hypotension requiring pressor agents at screening.

5. Pulmonary Pathology:

   1. History of severe lung disease, including significant bronchiectasis, emphysema, or advanced interstitial lung disease (ILD) at baseline.
   2. Resting oxygen saturation (SpO2 <92%).

6. Concomitant Therapy: Requirement for long-term glucocorticoids or immunosuppressive therapy for conditions other than SLE.

7. Infections: Active infections requiring systemic treatment or uncontrollable infections (bacterial, fungal, or viral) within 1 week before screening.

8. Transplantation/GVHD: Solid organ or hematopoietic stem cell transplantation within 3 months before screening; or presence of Grade 2 or higher acute graft-versus-host disease (GVHD) within 2 weeks of screening.

9. Viral and Serological Markers:

   1. Positive HBsAg or HBcAb with detectable HBV-DNA.
   2. Positive HCV antibody with detectable HCV-RNA.
   3. Positive HIV antibody, syphilis test, or detectable CMV-DNA.

10. Other Clinical Conditions:

    1. Macrophage activation syndrome (MAS) within 1 month before screening.
    2. Vaccination with a live vaccine within 4 weeks before screening.
    3. Malignancies or other severe systemic diseases.

11. Pregnancy: Positive blood pregnancy test at screening.

12. Trial Participation: Enrollment in another clinical trial within 3 months prior to this study.

13. Investigator Discretion: Any other condition that, in the opinion of the investigator, makes the subject unsuitable for the study or puts them at undue risk.