Study to Evaluate the Safety and Preliminary Efficacy of CD19 CAR-T Cell Therapy (TranspoCART19) in Patients With Refractory Lupus Nephritis

A National Multicenter Phase I/IIa Study to Evaluate the Safety and Preliminary Efficacy of CD19 CAR-T Cell Therapy (TranspoCART19) in Patients With Refractory Lupus Nephritis.

The goal of this clinical trial is to evaluate the safety and preliminary efficacy of CD19 CAR-T cell therapy (TranspoCART19) in adults with refractory lupus nephritis. Lupus nephritis is a serious kidney complication of systemic lupus erythematosus that may not respond adequately to standard treatments.

The main questions this study aims to answer are:

• Is TranspoCART19 safe and tolerable in patients with refractory lupus nephritis?
• Can TranspoCART19 induce complete or partial clinical and immunological remission?

Participants will:

• Undergo leukapheresis to collect immune cells for manufacturing TranspoCART19.
• Receive lymphodepleting chemotherapy before treatment.
• Receive a single fractionated infusion of TranspoCART19.
• Attend regular follow-up visits for safety, disease activity, kidney function, immune response, and quality-of-life assessments for up to 24 months, with long-term safety follow-up after study completion.

This is a Phase I/IIa, academic, multicenter, open-label, single-arm clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of TranspoCART19 in adult patients with refractory lupus nephritis.

TranspoCART19 is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy manufactured using Sleeping Beauty transposon technology. The CAR construct incorporates an anti-CD19 FMC63 single-chain variable fragment, a 4-1BB co-stimulatory domain, a CD3ζ signaling domain, and a truncated human epidermal growth factor receptor (hEGFRt) safety switch.

Eligible participants will undergo leukapheresis for collection of peripheral blood mononuclear cells. Following manufacturing of the investigational product, participants will receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide, or bendamustine when clinically indicated, prior to administration of TranspoCART19.

TranspoCART19 will be administered intravenously at a target dose of 1 × 10^6 CAR-T cells/kg body weight using a fractionated infusion strategy consisting of 10%, 30%, and 60% dose fractions. Participants will remain under close monitoring for early and late treatment-related toxicities.

The primary objective is to evaluate the safety and tolerability of TranspoCART19 during the early post-infusion period. Safety assessments include adverse events, serious adverse events, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), severe infections, prolonged cytopenias, and hypogammaglobulinemia.

Secondary objectives include evaluation of clinical, renal, histological, and immunological responses; hematologic and immune reconstitution; CAR-T cell persistence and kinetics; corticosteroid and immunosuppressive treatment withdrawal; systemic lupus erythematosus disease activity; and health-related quality of life.

Approximately 10 participants will be enrolled. Participants will be followed for 24 months after infusion, and long-term safety monitoring will continue for up to 15 years in accordance with recommendations for genetically modified cellular therapies.

Inclusion Criteria:

1. Ability and willingness to provide written informed consent.
2. Adults aged ≥18 and ≤65 years with a diagnosis of systemic lupus erythematosus (SLE) according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria.
3. Positive antinuclear antibody (ANA) result at a titer >1:80, or positive anti-double stranded DNA (anti-dsDNA), or positive anti-Smith (anti-Sm) antibodies at screening.
4. Diagnosis of class III or IV proliferative lupus nephritis, with or without concomitant class V disease, confirmed by renal biopsy demonstrating active lupus nephritis according to the 2018 ISN/RPS classification.
5. Evidence of refractory or treatment-resistant lupus nephritis according to GLOSEN criteria.
6. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² during the screening period.
7. Urine protein-to-creatinine ratio (UPCR) >0.7 g/g, urine albumin-to-creatinine ratio (UACR) >0.5 g/g, proteinuria >0.7 g/24 h, or albuminuria >0.5 g/24 h at screening with evidence of active lupus nephritis.
8. Stable treatment with an ACE inhibitor, angiotensin receptor blocker and/or mineralocorticoid receptor antagonist (with or without an SGLT2 inhibitor) for at least 3 months prior to screening, unless contraindicated or not tolerated.
9. Adequate venous access and no contraindication to leukapheresis.
10. Women of childbearing potential must have a negative pregnancy test at screening, prior to lymphodepletion and prior to infusion, and must agree to use highly effective contraception. Sexually active men must agree to use condoms and comply with protocol-specified reproductive precautions.
11. Completion of recommended vaccinations, including SARS-CoV-2 vaccination/immunization, before study treatment.
12. Ability and willingness to comply with all study procedures and follow-up requirements.

Exclusion Criteria:

1. Planned initiation of renal replacement therapy during the study period or eGFR <30 mL/min/1.73 m².

2. Severe organ dysfunction, including:

   • Left ventricular ejection fraction (LVEF) <40%.
   • Severe cardiac disease, including recent ischemic heart disease, NYHA class III-IV heart failure, uncontrolled arrhythmias, or severe lupus-related cardiac involvement.
   • Significant hepatic impairment (ALT or AST >1.5× ULN, total bilirubin >1.5× ULN except specified exceptions, INR >1.5).
   • Inadequate hematopoietic reserve (absolute neutrophil count ≤1000/µL, platelets <75,000/µL, leukocytes <3000/µL, lymphocytes ≤300/µL, hemoglobin <8 g/dL).
   • Oxygen saturation <92% on room air.
   • Severe pulmonary disease with compromised respiratory reserve.

3. Active infection requiring treatment during screening or before lymphodepletion.

4. Positive screening for HIV, hepatitis C virus, hepatitis B virus, or evidence of active tuberculosis.

5. Grade ≥2 thromboembolic event within 4 weeks before screening.

6. History of progressive multifocal leukoencephalopathy (PML) or symptoms suggestive of PML.

7. Requirement for systemic glucocorticoids at doses ≥30 mg/day prednisone equivalent.

8. Previous treatment with anti-CD19 CAR-T therapy.

9. Known hypersensitivity or contraindication to TranspoCART19, fludarabine, cyclophosphamide, bendamustine, or required concomitant medications.

10. Concurrent systemic autoimmune disease requiring immunosuppressive therapy independent of SLE treatment.

11. Current or previous malignancy, except adequately treated non-melanoma skin cancer, carcinoma in situ, or malignancy in complete remission for more than 3 years.

12. Previous solid organ transplantation, hematopoietic stem cell transplantation, or bone marrow transplantation.

13. Planned major surgery within one year after study treatment.

14. Receipt of live vaccines within 30 days before administration of the investigational product.

15. Current drug or alcohol abuse that may interfere with study participation.

16. Any severe or uncontrolled medical or psychiatric condition that, in the investigator's opinion, would increase risk or interfere with study participation.

17. Pregnancy or breastfeeding.

18. Women of childbearing potential unwilling to use highly effective contraception throughout the study period.

19. Sexually active men unwilling to use condoms and follow reproductive precautions required by the protocol.

20. Participation in another interventional clinical trial within 90 days before informed consent or receipt of another investigational product within the protocol-specified washout period.

21. Inability or unwillingness to provide informed consent or comply with study requirements.