Anti-CD19 CAR-NK Cells in Refractory/Relapsed Systemic Lupus Erythematosus

A Clinical Study of Anti-CD19 CAR-NK Cells in the Treatment of Refractory/Relapsed Systemic Lupus Erythematosus

This study is a single-center, open-label, single-arm, dose-escalation trial. The aim of this study is to investigate the safety and efficacy of anti-CD19 CAR-NK cells in patients with refractory/relapsed systemic lupus erythematosus.

Study Overview

• Status: Not yet recruiting
• Conditions: Systemic Lupus Erythematosus
• Intervention / Treatment: Drug: anti-CD19 CAR-NK cells

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Huaxiang Wu, PhD; Phone Number: 86-13757118395; Email: wuhx8855@zju.edu.cn

Study Locations

• China
  • Hangzhou, China, 310016
    • The Second Affiliated Hospital of Zhejiang University School of Medicine
    • Contact: Huaxiang Wu, PhD; Phone Number: 86-13757118395

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Voluntarily participate in this clinical study, sign an informed consent form, have good compliance, and cooperate with follow-up;
• Age range from 18 to 65 years old, regardless of gender;
• Fulfilling the 2019 ACR/EULAR classification criteria of SLE;
• Presence of anti-dsDNA or anti-Sm antibodies and decreased C3 or C4 levels;
• SELENA-SLEDAI≥8；
• Subject has ≥ 1 organ system with BILAG-2004 Class A mobility score or ≥ 2 organ systems with BILAG-2004 Class B mobility score prior to screening;
• Routine treatment is ineffective or the disease relapses after remission. Definition of routine treatment: use more than two drugs, including glucocorticoid (more than 1mg/kg/d), and any two or more of the following immunomodulatory drugs for more than 6 months: cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate, leflunomide, tacrolimus, ciclosporin, and biological agents, including rituximab, belizumab, or telitacicept；
• Hemoglobin ≥ 85g/L; white blood cell count ≥ 3 × 10^9/L；neutrophil count ≥ 1.5 × 10^9/L; platelets ≥ 50 × 10^9/L;
• The functions of important organs are basically normal: ALT ≤ 2 × ULN; AST ≤ 2 × ULN; eGFR ≥ 60ml/min/1.73m2; total bilirubin ≤2.0 mg/dL; cardiac function: left ventricular ejection fraction (LVEF) ≥ 50%; non-oxygenated blood oxygen saturation >94%; prothrombin time (PT) ≤ 1.5 × ULN；international standardized ratio (INR) ≤ 1.5 × ULN；
• Females of childbearing potential must use effective contraception during the study. In addition, subjects must not donate eggs during the study and for at least 90 days after the last dose of study treatment；

Exclusion Criteria:

• History of severe allergy or known hypersensitivity to any of the active ingredients of the cell product；
• Pregnant (or lactating) women;
• Severe lupus nephritis (defined as serum creatinine > 2.5 mg/dL or 221 μmol/L), treatment with hemodialysis within 8 weeks prior to screening；
• Other lupus crises, such as active central nervous system lupus, severe hemolytic anemia, severe thrombocytopenic purpura, severe agranulocytosis, severe myocardial damage, severe lupus pneumonia or pulmonary hemorrhage, severe lupus hepatitis, and severe vasculitis within 8 weeks prior to screening；
• Combined with other autoimmune diseases requiring systemic therapy;
• Clinically significant central nervous system diseases or pathological changes not caused by lupus prior to screening, including but not limited to: cerebrovascular accident, aneurysm, epilepsy, convulsions/convulsions, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis;
• Abnormal test results for hepatitis B or C indicate the presence of an active or chronic infection, including positive HBsAg or positive HBcAb with HBV DNA levels exceeding the normal upper limit，positive hepatitis C antibody and detectable HCV RNA；positive serology for human immunodeficiency virus (HIV) or a known history of HIV infection；
• Cytomegalovirus DNA levels and EB (Epstein-Barr) virus DNA levels in the peripheral blood exceeding the normal upper limits；
• Active or latent tuberculosis；
• Presence of uncontrollable bacterial, fungal, viral or other infections, requiring antibiotic therapy;
• Acquired and congenital immunodeficiency diseases；
• IgA deficiency;
• Other uncontrolled diseases: acute or chronic diseases that are clinically unstable or have not been effectively controlled and are not related to SLE；
• History of malignant diseases such as malignant tumors, except for adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, superficial bladder cancer, breast cancer;
• Any active skin disease that may interfere with the study assessment of SLE, including but not limited to psoriasis, dermatomyositis, systemic sclerosis, non-LE cutaneous lupus manifestations (eg, cutaneous vascular disease, periungual telangiectasia, fingertip sclerosis, rheumatoid nodules, erythema multiforme, leg ulcers) or drug-induced lupus；
• Prior treatment with cell therapy or any prior gene therapy product；
• Contraindication to cyclophosphamide in combination with fludarabine;
• Prior CD19-targeted therapy;
• Received live vaccine treatment within 4 weeks prior to screening;
• Subjects who have undergone major surgery within 8 weeks prior to screening, or who are scheduled to have surgery during the trial；
• Have received B-cell targeted therapy within 4 weeks prior to screening;
• Have received immunosuppressants within 1 week prior to screening;
• Have received plasmapheresis or intravenous immunoglobulin within 3 months prior to screening;
• Have participated in other clinical studies within 3 months prior to screening;
• History of vital organ transplantation (eg, heart, lung, kidney, liver) or hematopoietic stem cell/or bone marrow transplantation；
• Situations in which investigators consider it inappropriate to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: anti-CD19 CAR-NK cells; To evaluate the safety and efficacy of anti-CD19 CAR-NK cells in patients with refractory/relapsed systemic lupus erythematosus. All subjects will receive fludarabine/cyclophosphamide lymphodepletion followed by anti-CD19 CAR-NK cells infusion on Day 0, 7, and 14.	Drug: anti-CD19 CAR-NK cells; Patients will receive Fludarabine (25 mg/m2 per day) and Cyclophosphamide (500mg/m2 per day) on day -5, -4, and -3. Doses of 2×10^6/kg, 3×10^6/kg, 4×10^6/kg anti-CD19 CAR-NK cells will be infused in each group on Day 0, 7, and 14 using the "3 + 3" dose-escalation strategy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of subjects with DLT	DLT definition is dose-limiting toxicity.	Within 28 days after anti-CD19 CAR-NK cells infusion
The proportion of subjects with adverse events	Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs as assessed by CTCAE v5.0.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with Systemic Lupus Erythematosus Responder Index-4 (SRI-4) response	Proportion of patients with SRI-4 response: including SELENA-SLEDAI ≥4-Point improvement, BILAG 2004 with no new A domain score AND no more than 1 new B domain scores, PGA with No worsening (<0.3-point increase).	4, 8, 12, 16, 20, 24, 36 and 52 weeks after infusion
Proportion of participants achieving definition of remission in SLE (DORIS) remission	The Definition of Remission in SLE (DORIS) is a standardized criterion to clearly define what constitutes remission in patients with systemic lupus erythematosus.	4, 8, 12, 16, 20, 24, 36 and 52 weeks after infusion
Proportion of participants achieving Lupus Low Disease Activity State (LLDAS)	The Lupus Low Disease Activity State (LLDAS) is a clinical treatment target designed for patients with systemic lupus erythematosus. It represents a state where the disease activity is kept at a low level, aiming to minimize symptoms and prevent long-term damage caused by the disease.	4, 8, 12, 16, 20, 24, 36 and 52 weeks after infusion
Changes in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2000) score from baseline	Assessment of SLEDAI-2000 from baseline administration at various timepoints up to month 12 follow up visit.	Within 12 months after anti-CD19 CAR-NK cell infusion
Changes in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score from baseline	Assessment of SELENA-SLEDAI from baseline administration at various timepoints up to month 12 follow up visit.	Within 12 months after anti-CD19 CAR-NK cell infusion
Changes in the British Isles Lupus Assessment Group 2004 index (BILAG-2004) from baseline	Assessment of BILAG-2004 from baseline administration at various timepoints up to month 12 follow up visit.	Within 12 months after anti-CD19 CAR-NK cell infusion
Changes in the Physician Global Assessment (PGA) from baseline	Assessment of PGA from baseline administration at various timepoints up to month 12 follow up visit.	Within 12 months after anti-CD19 CAR-NK cell infusion
Change in proteinuria measured by 24h proteinuria or urine protein creatinine ratio (UPCR) from baseline	Assessment of 24h proteinuria or urine protein creatinine ratio (UPCR) from baseline administration at various timepoints up to month 12 follow up visit.	Within 12 months after anti-CD19 CAR-NK cell infusion
Changes in level of anti-nuclear antibody (ANA) in peripheral blood from baseline	Assessment of ANA from baseline administration at various timepoints up to month 12 follow up visit.	Within 12 months after anti-CD19 CAR-NK cell infusion
Changes in levels of complement C3 and C4 in peripheral blood from baseline	Assessment of C3 and C4 from baseline administration at various timepoints up to month 12 follow up visit.	Within 12 months after anti-CD19 CAR-NK cell infusion
CMAX of anti-CD19 CAR-NK cells	CMAX is defined as the highest concentration of anti-CD19 CAR-NK cell expansion in the peripheral blood.	3 months
TMAX of anti-CD19 CAR-NK cells	TMAX is defined as the time to reach the highest concentration of anti-CD19 CAR-NK cell expansion in the peripheral blood.	3 months

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Investigators: Principal Investigator: Huaxiang Wu, Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): May 31, 2026

Study Registration Dates

• First Submitted: May 13, 2024
• First Submitted That Met QC Criteria: May 17, 2024
• First Posted (Actual): May 20, 2024

Study Record Updates

• Last Update Posted (Actual): May 20, 2024
• Last Update Submitted That Met QC Criteria: May 17, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Connective Tissue Diseases; Lupus Erythematosus, Systemic
• Other Study ID Numbers: 2024-0530

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No