A Clinical Study of CD19 CAR-T in Refractory/Moderate-to-severe Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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The purpose of the study is to explore the safety and efficacy of CD19 CAR-T in refractory/moderately severe systemic lupus erythematosus.

Detailed Description
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The prognosis of patients with refractory/moderate-to-severe 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 refractory/moderate-to-severe 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 refractory/moderate-to-severe SLE. Patients with refractory/moderate-to-severe 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.

Official Title
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A Single-center Clinical Study Evaluating the Safety and Efficacy of CD19 CAR-T in Refractory/Moderate-to-severe Systemic Lupus Erythematosus

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Biological: CD19 CAR-T cell infusion


Participation Criteria
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Eligibility Criteria
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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; refractory/moderate-to-severe SLE needs to meet the following criteria at screening: SELENA-SLEDAI score ≥ 8 points; PGA ≥ 1 points; BILAG-2004 organ system scores of at least 1 A or 2 B; Positive test results for at least one of the following autoantibodies at screening: antinuclear antibodies (ANA) immunofluorescence assay at a titer of ≥1:80; anti-dsDNA; or anti-Smith (anti-Sm); 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; History of other lupus crisis 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 IgA deficiency at screening; Subjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and HBV DNA titer in peripheral blood higher than the lower limit of research institution's test range; Subjects with positive hepatitis C virus (HCV) antibodies; Subjects with positive human immunodeficiency virus (HIV) antibodies; Subjects tested positive for syphilis; Subjects with a Cytomegalovirus (CMV) DNA quantitation level that are higher than the lower limit of the institution's test range; Subjects with an Epstein-Barr virus (EBV) DNA quantitation level that are higher than the lower limit of the institution's test range; 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 intra-articular, intramuscular or intravenous glucocorticoids within 4 weeks prior to screening; Have received any commercially available Janus kinase inhibitor or Bruton tyrosine kinase inhibitor within 12 weeks 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; Have received cyclophosphamide and chlorambucil with 6 months before 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm<br>Participants will receive CD19 CAR-T cell intravenous infusion | Biological: CD19 CAR-T cell infusion<br>* CD19 CAR-T cell intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Safety and tolerability will be assessed by incidence and severity of adverse events (AEs) and serious AEs (SAEs). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are graded by ASTCT criteria, other AEs are assessed by CTCAE V5.0 criteria | Within 2 years after CD19 CAR-T cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) | Concentration of CD19 CAR-T cells in peripheral blood will be evaluated | Within 2 years after CD19 CAR-T cell infusion | 
| Pharmacodynamics (PD) | Pharmacodynamics (PD) will be assessed by levels of cytokines (IL-2、IL-6、IL-10、IFN-γ) in peripheral blood | Within 28 days after CD19 CAR-T cell infusion | 
| Proportion of subjects with SRI-4 response | SRI-4 response is defined as: 1) the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score decrease by no less than 4 points from baseline; 2) the British Isles Lupus Assessment Group (BILAG) score with no new A domain score and no more than 1 new B domain score compared to baseline; 3) the Physician Global Assessment (PGA) score increase less than 0.3 point from baseline | Within 2 years after CD19 CAR-T cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24) | 
| Changes in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score from baseline | Range [0, 105]，higher score represents worse disease activity | Within 2 years after CD19 CAR-T cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24) | 
| Changes in the Physician Global Assessment (PGA) score from baseline | Range [0, 3]，higher score represents worse disease activity | Within 2 years after CD19 CAR-T cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24) | 
| Changes in immunological indexes from baseline | Serum IgA, IgG, IgE and IgM will be evaluated | Within 2 years after CD19 CAR-T cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24) | 
| Changes in level of anti-nuclear antibody (ANA) in peripheral blood from baseline | To evaluate SLE disease activity | Within 2 years after CD19 CAR-T cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24) | 
| Changes in level of anti-double stranded DNA (dsDNA) antibody in peripheral blood from baseline | To evaluate SLE disease activity | Within 2 years after CD19 CAR-T cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24) | 
| Changes in levels of complement C3 in peripheral blood from baseline | To evaluate SLE disease activity | Within 2 years after CD19 CAR-T cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24) | 
| Changes in levels of complement C4 in peripheral blood from baseline | To evaluate SLE disease activity | Within 2 years after CD19 CAR-T cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory/moderately to severe systemic lupus erythematosus, CAR-T, CD19