A Clinical Study of CD19 Universal CAR-γδT Cells in Refractory/Moderate-to-severe Systemic Lupus Erythematosus
Study Details
Study Description
Brief Summary
The purpose of the study is to explore the safety and efficacy of CD19 Universal CAR-γδT cells in refractory/moderately severe systemic lupus erythematosus.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
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 Universal CAR-γδT cells 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 Universal CAR-γδT cells intravenous infusion and follow-up visits of up to 2 years after enrollment.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Experimental Arm Participants will receive CD19 Universal CAR-γδ T Cells intravenous infusion |
Biological: CD19 Universal CAR-γδ T Cells
Intravenous infusion of CD19 Universal CAR-γδ T Cells
|
Outcome Measures
Primary Outcome Measures
- Safety and tolerability [Within 2 years after CD19 Universal CAR-γδT cell infusion]
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
Secondary Outcome Measures
- Pharmacokinetics (PK) [Within 2 years after CD19 Universal CAR-γδT cell infusion]
Concentration of CD19 Universal CAR-γδT cell in peripheral blood will be evaluated
- Pharmacodynamics (PD) [Within 28 days after CD19 Universal CAR-γδT cell infusion]
Pharmacodynamics (PD) will be assessed by levels of cytokines (IL-2、IL-6、IL-10、IFN-γ) in peripheral blood
- Proportion of subjects with SRI-4 response [Within 2 years after CD19 Universal CAR-γδT cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24]
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.
- Changes in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score from baseline [Within 2 years after CD19 Universal CAR-γδT cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24)]
Range [0, 105]，higher score represents worse disease activity
- Changes in the Physician Global Assessment (PGA) score from baseline [Within 2 years after CD19 Universal CAR-γδT cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24)]
Range [0, 3]，higher score represents worse disease activity
- Changes in immunological indexes from baseline [Within 2 years after CD19 Universal CAR-γδT cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24)]
Serum IgA, IgG, IgE and IgM will be evaluated
- Changes in level of anti-nuclear antibody (ANA) in peripheral blood from baseline [Within 2 years after CD19 Universal CAR-γδT cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24)]
To evaluate SLE disease activity
- Changes in level of anti-double stranded DNA (dsDNA) antibody in peripheral blood from baseline [Within 2 years after CD19 Universal CAR-γδT cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24)]
To evaluate SLE disease activity
- Changes in levels of complement C3 in peripheral blood from baseline [Within 2 years after CD19 Universal CAR-γδT cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24)]
To evaluate SLE disease activity
- Changes in levels of complement C4 in peripheral blood from baseline [Within 2 years after CD19 Universal CAR-γδT cell infusion (day 14, day 28, month 3, month 6, month 9, month 12, month 18, month 24)]
To evaluate SLE disease activity
Eligibility Criteria
Criteria
Inclusion Criteria:
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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;
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Age range from 18 to 70 years old, regardless of gender;
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Body weight ≥ 40kg;
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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;
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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;
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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);
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Have received at least 8 weeks of standardized treatment for SLE prior to screening;
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Female participants need to have a negative pregnancy test, and participants agree to take effective contraceptive measures throughout the study.
Exclusion Criteria:
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Known hypersensitivity to prednisone, immunosuppressive agents;
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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;
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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;
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Presence of SLE or non-SLE related central nervous system diseases or pathological changes within 8 weeks prior to screening;
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History of other lupus crisis prior to screening;
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Previous or current diagnosis of non-SLE-related inflammatory arthropathy or skin diseases;
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Previous or current diagnosis of severe vasculitis due to other diseases excluding SLE;
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History of vital organ transplantation or hematopoietic stem cell/or bone marrow transplantation;
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Have received plasmapheresis, hemodialysis, intravenous immunoglobulin within 14 days prior to screening;
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Other autoimmune diseases requiring systemic therapy;
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Subjects with IgA deficiency at screening;
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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;
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Active or latent tuberculosis at screening (can be enrolled if appropriately treated);
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Any of severe laboratory abnormalities in liver function, renal function, bone marrow function, coagulation function, pulmonary function, cardiac function at screening;
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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;
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Severe heart diseases;
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Severe hepatobiliary disease;
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Presence of medical conditions that are obviously unstable or not effectively treated;
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Presence of uncontrollable bacterial, fungal, viral or other infections, requiring antibiotic therapy;
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Have received live/attenuated vaccination within 4 weeks prior to screening or plan to receive live/attenuated vaccination throughout the study;
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Have received intra-articular, intramuscular or intravenous glucocorticoids within 4 weeks prior to screening;
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Have received any commercially available Janus kinase inhibitor or Bruton tyrosine kinase inhibitor within 12 weeks prior to screening;
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Have received B-cell targeted therapy prior to screening;
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Have received a biologic agent other than B-cell targeted therapy within 5 half-lives prior to screening;
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Have received cyclophosphamide and chlorambucil with 6 months before screening;
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Previous received therapies with CAR-T cells or other genetically modified T cells;
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Have received therapeutic dose of corticosteroids within 7 days prior to leukapheresis or within 72 hours prior to infusion;
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Have received any other study drugs for SLE within 4 weeks prior to leukapheresis;
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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;
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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;
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History of ≥ grade 2 bleeding within 4 weeks prior to screening or need for long-term continuous anticoagulant therapy;
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Subjects with severe mental illness;
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Alcoholics or subjects with a history of drug abuse;
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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;
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History of malignancy；
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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.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Wuhan Union Hospital, China
- Guangzhou Bio-gene Technology Co., Ltd
Investigators
- Principal Investigator: Qiubai Li, Professor, Department of Rheumatology, Wuhan Union Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- UHCT230443