Safety and Efficacy of Metabolically Armed CD19 CAR-T Cells (Meta10-19) in the Treatment of Moderate to Severe Active SLE Clinical Research

A Study of Metabolically Armed CD19 CAR-T Cells Therapy for Patients With Moderate to Severe Active Systemic Lupus Erythematosus

This is a single arm, open-label study. This study is indicated for moderate to severe active systemic lupus erythematosus. The selections of dose levels and the number of subjects are based on clinical trials of similar foreign products and our earlier disclosed clinical trials .

1. Main research objectives:

   To evaluate the safety and efficacy of metabolically armed CD19 CAR-T Cells in the treatment of moderate to severe active SLE.
2. Secondary research objectives:

(1) To evaluate the pharmacokinetic (PK) and pharmacodynamics(PD) characteristics of metabolically armed CD19 CAR-T Cells after infusion and their relationship with the number of B cells.

(2) To evaluate the effects of the concentration of autoimmune antibodies and complement after infusion of metabolically armed CD19 CAR-T Cells.

Eligibility Criteria:
Inclusion Criteria:

* All subjects or guardians must sign an informed consent form approved by the Ethics Committee in person before commencing any screening process;
* Be over 18 years of age, male or female;
* A diagnosis of SLE according to the 2012 systemic lupus international collaborating clinics(SLICC);
* The history of SLE prior to screening was at least 6 months, and the disease remained active at least 2 months after the use of a stable standard SLE regimen prior to screening:

  1. Conventional regimens for SLE are corticosteroids and one or more immunomodulatory drugs over 6 months；
  2. Oral corticosteroids must meet the following requirements:

     * Prednisone (or equivalent) ≥7.5 mg/ day, and ≤60 mg/ day；
     * There is no minimum daily dose requirement for corticosteroids when used in combination with immunosuppressants；
     * At least 8 weeks of treatment prior to screening, and the dose must be kept stable for \> 2 weeks.
* Screening is positive for antinuclear antibodies, and/or anti-DS-DNA antibodies, and/or anti-Smith antibodies；
* SELENA-SLEDAI score ≥8 during the screening period. Score ≥6 for SELENA-SLEDAI clinical symptoms (except for low complement and/or anti-DS-DNA antibodies) if low complement and/or anti-DS-DNA antibody score is present；
* Women of childbearing age and all male patients must consent to use a effective contraception for at least 12 months after Meta10-19 infusion and until two consecutive PCR tests show no more CAR T cells in vivo;
* CD19 expression was positive by or flow cytometry ;
* Organ function：

  1. Complete blood count (CBC) test \[the following criteria should be met within 24 hours prior to apheresis, and supportive treatment such as transfusion, platelet transfusion, cell growth factor (except recombinant erythropoietin) should be avoided within 7 days prior to detection\]

     * Lymphocyte count ≥ 0.5×109/L (except for those receiving bridging chemotherapy);
     * Platelet count ≥ 25×109/L;
     * Hemoglobin ≥ 70.0 g/L
  2. Blood Biochemistry:

     * Serum creatinine (Scr) ≤ 1.5 x ULN, or
     * endogenous creatinine clearance ≥ 40 mL/min (using Cockcroft-Gault formula);
     * alanine aminotransferase (ALT) ≤ 2.5 x ULN;
     * aspartate aminotransferase (AST) ≤ 2.5 ×ULN;
     * Total bilirubin (TBIL) ≤ 2 ×ULN; Subjects with total bilirubin \< 3 × ULN and direct bilirubin \< 1.5× ULN with Gilbert-.Meulengracht syndrome could be included;
     * Serum lipase and amylase ≤ 1.5×ULN;
     * Alkaline phosphatase (ALP) ≤ 2.5 ×ULN;
     * In case of bone or liver metastasis, AST, ALT and ALP ≤ 5 ×ULN;
     * Prothrombin time (PT) extended ≤ 4 s, fibrinogen ≥ 1 g/L, activated partial thromboplastin time (APTT) ≤ 1.5 ×ULN;
  3. Pulmonary function: ≤CTCAE grade 1 dyspnea and oxygen saturation of blood (SaO2) \> 91% in indoor air environment..
* Hemodynamic stability was determined by echocardiography or multichannel radionuclide angiography (MUGA) and LVEF ≥45％.

Exclusion Criteria:

* Severe lupus nephritis (defined as proteinuria \> 6 g/24h or serum creatinine \> 2.5 mg/dL or 221 μmol/L), treatment with active nephritis with Prohibited drugs, hemodialysis, or prednisone ≥100 within 8 weeks prior to screening mg/d or equivalent glucocorticoid therapy ≥14 days.
* 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.
* 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.
* Combined with other autoimmune diseases, systematic treatment is needed.
* History of major organ transplantation (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/bone marrow transplantation.
* IgA deficiency was present during screening (serum IgA level \< 10 mg/dL).
* Other conditions that the investigator considered should not be enrolled in this clinical study.