A Clinical Study of CD19 CAR-T in Active Systemic Lupus Erythematosus

A Single-center Clinical Study Evaluating the Safety and Efficacy of CD19 CAR-T in Active Systemic Lupus Erythematosus

The purpose of the study is to explore the safety and efficacy of CD19 CAR-T in active systemic lupus erythematosus.

The prognosis of patients with active systemic lupus erythematosus (SLE) remains poor, due to two major therapeutic obstacles: (1) current treatment strategies including glucocorticoids, immunosuppressive agents, biological agents, are still difficult to achieve disease control, making the disease condition of some patients continue to be active or even worse; (2) some patients are unable to wean themselves off glucocorticoid and face the risk of numerous adverse effects caused by long-term glucocorticoid dependence, such as glucocorticoid-related diabetes, femoral head necrosis, hypertension, stress ulcers, and infection, etc. Therefore, there is a strong unmet clinical need for more effective treatment for patients suffering from active SLE. Several preclinical studies have shown the efficacy of CAR-T cell treatment in SLE. The aim of this study is to investigate the safety, tolerability, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of CD19 CAR-T cell therapy in active SLE. Patients with active SLE will be invited to participate in the study, to receive CD19 CAR-T intravenous infusion and follow-up visits of up to 2 years after enrollment.

Inclusion Criteria:

1. Participants or their guardians understand and voluntarily sign the informed consent form, and be able to complete all the documents, procedures, follow-up examinations and treatments specified in the study protocol, with good compliance;

2. Age range from 18 to 70 years old, regardless of gender;

3. Body weight ≥ 40kg;

4. Participants diagnosed with SLE according to the American College of Rheumatology (ACR) 1997 revised criteria for SLE at least 24 weeks prior to signing the informed consent form;

5. Active SLE needs to meet the following criteria at screening:

   SELENA-SLEDAI score ≥ 6 points; PGA ≥ 1 points;

6. Have received at least 8 weeks of standardized treatment for SLE prior to screening;

7. Female participants need to have a negative pregnancy test, and participants agree to take effective contraceptive measures throughout the study.

Exclusion Criteria:

1. Known hypersensitivity to prednisone, immunosuppressive agents;
2. Diagnosis of active severe lupus nephritis within 8 weeks prior to screening, requiring medications prohibited by the research protocol for active nephritis, hemodialysis or prednisone ≥ 100 mg/d, or equivalent glucocorticoid therapy for ≥14 days;
3. Suicidal ideation within the past 6 months based on assessment by Columbia-Suicide Severity Rating Scale (C-SSRS) at screening; or any suicidal behaviors within the past 12 months or recurrent suicidal behaviors during the subject's lifetime;
4. Presence of SLE or non-SLE related central nervous system diseases or pathological changes within 8 weeks prior to screening;
5. Existence of other lupus crisis within 8 weeks prior to screening;
6. Previous or current diagnosis of non-SLE-related inflammatory arthropathy or skin diseases;
7. Previous or current diagnosis of severe vasculitis due to other diseases excluding SLE;
8. History of vital organ transplantation or hematopoietic stem cell/or bone marrow transplantation;
9. Have received plasmapheresis, hemodialysis, intravenous immunoglobulin within 14 days prior to screening;
10. Other autoimmune diseases requiring systemic therapy;
11. Subjects with active viral hepatitis B; Subjects with positive hepatitis C virus (HCV) antibodies; Subjects with positive human immunodeficiency virus (HIV) antibodies; Sujects with positive extracellular DNA quantification of cytomegalovirus (CMV); Sujects with positive extracellular DNA quantification of EB virus (EBV);Subjects tested positive for syphilis;
12. Active or latent tuberculosis at screening (can be enrolled if appropriately treated);
13. Any of severe laboratory abnormalities in liver function, renal function, bone marrow function, coagulation function, pulmonary function, cardiac function at screening;
14. History of severe allergy or known hypersensitivity to any of the active ingredients of the drugs, excipients, or rodent-derived products, xenoproteins included in this trial, or subjects with allergic constitution;
15. Severe heart diseases;
16. Severe hepatobiliary disease;
17. Presence of medical conditions that are obviously unstable or not effectively treated;
18. Presence of uncontrollable bacterial, fungal, viral or other infections, requiring antibiotic therapy;
19. Have received live/attenuated vaccination within 4 weeks prior to screening or plan to receive live/attenuated vaccination throughout the study;
20. Have received any commercially available Janus kinase inhibitor or Bruton tyrosine kinase inhibitor within 3 half-lives prior to screening;
21. Have received B-cell targeted therapy prior to screening;
22. Have received a biologic agent other than B-cell targeted therapy within 5 half-lives prior to screening;
23. Previous received therapies with CAR-T cells or other genetically modified T cells;
24. Have received therapeutic dose of corticosteroids within 7 days prior to leukapheresis or within 72 hours prior to infusion;
25. Have received any other study drugs for SLE within 4 weeks prior to leukapheresis;
26. Subjects that have undergone major surgery within 4 weeks prior to lymph depletion or those who are scheduled to undergo major surgery during the study period, or whose surgical wounds have not fully healed prior to enrollment;
27. Subjects that have donated blood for ≥ 400mL or had significant blood loss equivalent to at least 400mL within 4 weeks prior to screening, or have received a blood transfusion within 8 weeks, or plan to donate blood during the study period;
28. History of ≥ grade 2 bleeding within 4 weeks prior to screening or need for long-term continuous anticoagulant therapy;
29. Subjects with severe mental illness;
30. Alcoholics or subjects with a history of drug abuse;
31. Female subjects who are pregnant or lactating, or intend to pursue pregnancy within 2 years after the cell infusion; male patients whose female sexual partners intend to conceive within 2 years after the cell infusion;
32. History of malignancy；
33. Patients that have contraindications to any of the study procedures or have other medical conditions that may expose them to unacceptable risk, in the judgment of the investigators and/or clinical criteria.