A Clinical Study 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

• 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;
• Age range from 18 to 70 years old, regardless of gender;
• Body weight ≥ 40kg;
• 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;
• Active SLE needs to meet the following criteria at screening:

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

• Have received at least 8 weeks of standardized treatment for SLE prior to screening;
• Female participants need to have a negative pregnancy test, and participants agree to take effective contraceptive measures throughout the study.

Exclusion criteria

• Known hypersensitivity to prednisone, immunosuppressive agents;
• 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;
• 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;
• Presence of SLE or non-SLE related central nervous system diseases or pathological changes within 8 weeks prior to screening;
• Existence of other lupus crisis within 8 weeks prior to screening;
• Previous or current diagnosis of non-SLE-related inflammatory arthropathy or skin diseases;
• Previous or current diagnosis of severe vasculitis due to other diseases excluding SLE;
• History of vital organ transplantation or hematopoietic stem cell/or bone marrow transplantation;
• Have received plasmapheresis, hemodialysis, intravenous immunoglobulin within 14 days prior to screening;
• Other autoimmune diseases requiring systemic therapy;
• 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;
• Active or latent tuberculosis at screening (can be enrolled if appropriately treated);
• Any of severe laboratory abnormalities in liver function, renal function, bone marrow function, coagulation function, pulmonary function, cardiac function at screening;
• 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;
• Severe heart diseases;
• Severe hepatobiliary disease;
• Presence of medical conditions that are obviously unstable or not effectively treated;
• Presence of uncontrollable bacterial, fungal, viral or other infections, requiring antibiotic therapy;
• Have received live/attenuated vaccination within 4 weeks prior to screening or plan to receive live/attenuated vaccination throughout the study;
• Have received any commercially available Janus kinase inhibitor or Bruton tyrosine kinase inhibitor within 3 half-lives prior to screening;
• Have received B-cell targeted therapy prior to screening;
• Have received a biologic agent other than B-cell targeted therapy within 5 half-lives prior to screening;
• Previous received therapies with CAR-T cells or other genetically modified T cells;
• Have received therapeutic dose of corticosteroids within 7 days prior to leukapheresis or within 72 hours prior to infusion;
• Have received any other study drugs for SLE within 4 weeks prior to leukapheresis;
• 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;
• 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;
• History of ≥ grade 2 bleeding within 4 weeks prior to screening or need for long-term continuous anticoagulant therapy;
• Subjects with severe mental illness;
• Alcoholics or subjects with a history of drug abuse;
• 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;
• History of malignancy；
• 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.