Treatment of Relapsed and/or Refractory AQP4-IgG Seropositive NMOSD by Tandem CAR T Cells Targeting CD19 and CD20

Treatment tested

• Corticosteroids & tanCART19/20

Other measures (6)

Inclusion Criteria: 1. Clinical diagnosis of neuromyelitis optica spectrum disorders (NMOSD) patients. 2. Patients with AQP4-IgG seropositive by cell-based assay. 3. Patients with corticosteroid treatment combined immunosuppressant (azathioprine or mycophenolate mofetil or rituximab) still recurrence. 4. Clinical evidence of at least 2 relapses in last 12 months or 3 relapses in the last 24 months with at least 1 relapse in the 12 months prior to the Screening. 5. Best corrected visual acuity(BCVA)\<20/60. 6. Normal bone marrow reserve function: neutrophils>1 500/mm3, Hemoglobin > 10g/dL, Platelet count > 100 000/mm3. 7. Normal liver and kidney function: Creatinine \< 2.5 mg/dl, ALT (alanine aminotransferase)/AST (aspartate aminotransferase) \< 3x normal, Bilirubin \< 2.0 mg/dl. 8. Successful test expansion of tanCART19/20 cells. 9. Adequate venous access for apheresis, and no other contraindications for leukapheresis. 10. Voluntary informed consent is given. Exclusion Criteria: 1. Pregnant or lactating women (The safety of this therapy on unborn children is not known, Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion). 2. Any serious, uncontrolled diseases (including, but not limit to, uncontrolled active infection, active hepatitis B or hepatitis C infection, HIV infection, unstable angina pectoris, congestive heart failure, serious arrhythmia). 3. Concurrent use of systemic steroids or immunosuppressant in the last two weeks. 4. Feasibility assessment during screening demonstrates \< 30% transduction of target lymphocytes, or insufficient expansion (\< 5-fold) in response to CD3/CD137 costimulation. 5. Other patients who are not suitable for CAR-T therapy judged by the biotherapy physician.

CAR-T therapy was proposed and has been recently used for cancer treatment. It has been hailed for its promising remission rates after early stage clinical trials for acute lymphoblastic leukemia. However, CAR-T therapy is seldom used for autoimmune diseases. Researchers only use it for the treatment of systemic lupus erythematosus (SLE). Neuromyelitis optica spectrum disorders (NMOSD), that include the neuromyelitis optica (NMO), are a group of inflammatory disorders of the central nervous system characterized by episodes of immune-mediated demyelination and axonal damage mainly involving optic nerves and spinal cord. NMO is characterized by the presence of an anti-Aquaporin-4 (AQP4) antibody, which can only be produced by differentiation of B cells to plasma cells. Because these anti-AQP4 antibodies may be pathogenic, B cells recognizing AQP4 may be directly involved in the disease process as well. B cells also play a role as potent antigen presenting cells in NMO. NMO has the characteristics of high recurrence rate and poor prognosis. In the conventional treatment options, NMOSD could be treated with corticosteroids and immunosuppressive drugs immunosuppressant (e.g. azathioprine, mycophenolate mofetil, rituximab). But these drugs could barely completely cure NMOSD. And now, chimeric antigen receptor modified T cell infusion maybe an effective treatment to solve these problems. The rationale for using CAR-T therapy in NMOSD is based on the known roles of B cells, antibody production and plasma cells in the pathophysiology of NMOSD. The strongest evidence of the importance of B cells in NMO comes from studies of B cell depletion, most commonly with anti-CD20 monoclonal antibody, rituximab. Emerging evidence indicates that peripheral B cells are activated during a relapse and plasmablast production of anti-AQP4 antibodies spikes. The investigators infuse tanCART19/20 to completely deplete B cells. The purpose of this study is to assess the safety and efficacy of this tanCART19/20 in the treatment of NMOSD.