Study of Ultra-Fast CD19 CAR-T Therapy for Refractory SLE

Official title

Study of Ultra-Fast Autologous CD19-targeted Chimeric Antigen Receptor T (CAR- T) Therapy for Refractory Systemic Lupus Erythematosus

Overview

This is an investigator-initiated trial aimed at assessing the safety and efficacy of ultra-fast autologous CD19-targeted CAR-T cells in the treatment of refractory systemic lupus erythematosus.

Detailed description

Systemic lupus erythematosus (SLE) is a serious autoimmune disease that can lead to extensive damage in multiple organs and systems, ultimately resulting in disability and even death.

Currently, the primary treatment for SLE relies on glucocorticoids and immunosuppressants to alleviate symptoms. However, due to the absence of a curative treatment, patients typically need to remain on medication indefinitely. In recent years, biological agents such as belimumab and rituximab have been introduced for the treatment of SLE, but these treatments cannot completely eliminate autoimmune B cells in the bone marrow, leading to unsatisfactory overall outcomes. Furthermore, discontinuing these drugs can lead to disease relapse, and there is still no cure for SLE, leaving patients facing the challenges of lifelong medication and an incurable disease.

CAR-T therapy is an adoptive cell therapy that uses genetic modification technology to reprogram T cells and eliminate target cells expressing diseaserelated antigens through antigen-specific recognition. Since 2019, CAR-T cell therapy has been successfully applied to autoimmune diseases. Clinical studies have demonstrated that CD19-targeted CAR-T cells hold significant therapeutic potential for SLE. Compared with traditional CAR-T cells, ultra-fast CAR-T, relying on an innovative CAR-T manufacturing system, can produce CAR-T cells in an extremely short period of time (with a preparation time of only 10 minutes).

The purpose of this study is to assess the safety and efficacy of the ultra-fast autologous CD19-targeted CAR-T cells in the treatment of refractory SLE.

Interventions

• Biological CD19 CAR-T cells
  Three dose groups (1.5×10\^5/kg, 5×10\^5/kg, 10×10\^5/kg) were set up, starting from the low dose group climbing to explore the safe and effective dose.

Primary outcome measures

• The safety of CAR-T cell therapy in patients with refractory SLE [Safety] [Time frame: 3 months]
• The changes from baseline in SLEDAI-2K [efficacy] [Time frame: 6 months]
• The changes from baseline in PGA [efficacy] [Time frame: 6 months]
• The changes from baseline in BILAG-2004 [efficacy] [Time frame: 6 months]
• The number of patients with SRI-4 response [efficacy] [Time frame: 3 months]
• The number of patients with LLDAS [efficacy] [Time frame: 6 months]
• The number of patients with DORIS [efficacy] [Time frame: 6 months]

Secondary outcome measures (11)

• The number of remission of lupus nephritis [efficacy] [Time frame: 6 months]
• The changes of anti-ds-DNA antibody after infusion [efficacy] [Time frame: 6 months]
• The changes of 24h urine protein after infusion [efficacy] [Time frame: 6 months]
• The changes of C3 and C4 after infusion [efficacy] [Time frame: 6 months]
• Cmax of CAR-T cells [PK parameter] [Time frame: 3 months]
• Tmax of CAR-T cells [PK parameter] [Time frame: 3 months]
• AUC28d/90d of CAR-T cells [PK parameter] [Time frame: 3 months]
• The degree of B cell depletion [PD parameter] [Time frame: 3 months]
• The concentration levels of IL-6 [PD parameter] [Time frame: 3 months]
• The concentration levels of CRP [PD parameter] [Time frame: 3 months]
• The concentration levels of ferritin [PD parameter] [Time frame: 3 months]

Eligibility criteria

Inclusion criteria

• Age: ≥ 5 years old, and no gender limitation;
• Diagnosed with SLE according to the 2019 EULAR/ACR SLE classification criteria, and still in moderate to severe disease activity despite ≥3M of high dose glucocorticoids(prednisone≥1mg/kg/d or other equivalent amount of other steriod), hydroxychloroquine and at least 2 DMARDs(include cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate, cyclosporin, tacrolimus, sirolimus, leflunomide, telitacicept, Beliumab, and rituximab) or intolerant to standard treatments;
• SLEDAI-2K score≥8 points;
• The functions of important organs are basically normal:

• Cardiac function: Left ventricular ejection fraction (LVEF) ≥55% with no obvious abnormality in electrocardiogram;
• Renal function: eGFR≥30mL/min/1.73m2;
• Liver function: AST and ALT≤3.0 ULN, total Bilirubin (TBIL) in serum ≤2.0×ULN;
• Lung function: no serious lung lesions, SpO2≥92%;
• Meet the standards of leukapheresis or intravenous blood collection, and no contraindication for leukapheresis;
• Negative pregnancy test for female subjects of childbearing age, and agree to take effective contraceptive measures the first year after CAR-T infusion;
• Participants or their guardians agrees to participate in the clinical trial and sign the informed consent form which indicating that he/she understands the purpose and procedure of the clinical trial and is willing to participate in the study.

Exclusion criteria

• Central nervous system (CNS) disease: CNS neurolupus requires intervention within 60 days);
• Severe acute nephritis: patients who have accepted or was undergoing renal replacement therapy within 3 months prior to transfusion; or in the investgator's opinion, patients who is likely to have significant kidney disease within 3 moths of the study which need high dose glucocorticoid (prednisone dose≥1mg/kg/day or equivalent amount of other steriod), cyclophosphamide, or mycophenolate mofetil treatment;
• Have a history of congenital heart disease or severe arrhythmias (including multisource frequent supraventricular tachycardia, ventricular tachycardia, etc.); or combined with moderate to massive pericardial effusion, serious myocarditis, etc; or patients with unstable vital signs who need hypertensive drugs;
• Uncontrollable infection, or active infection that requires systemic treatment within 3 months prior to screening;
• Received organ transplantation or hematopoietic stem cell transplantation within 3 months prior to screening, or ≥Grade 2 GVHD within 2 weeks prior to screening;
• Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer greater than the normal reference value range; or hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C virus (HCV) RNA titer greater than the normal reference value range; or positive for human immunodeficiency virus (HIV) antibodies; or syphilis test positive;
• Suffered from macrophage activation syndrome(MAS) within 1 month prior to screening (except for those whose safety risks have been ruled out by the researcher after treatment);
• Received CAR-T treatment (except for those whose safety risks have been ruled out by the researchers after treatment);
• Suffered from active pulmonary tuberculosis at screening;
• Received live vaccine within 4 weeks prior to screening;
• Positive in Blood pregnancy test;
• Previous or concurrent malignancy;
• Patients who participated in other clinical study within 3 months prior to screening;
• Any other conditions that the investigators deem it unsuitable for the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Children's Hospital of Zhejiang University School of Medicine — Hangzhou

Identifiers

NCT: NCT07233642 · PBC097

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗