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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
This study is being conducted to assess anti-CD19/20 CAR T cells safety and efficacy in treating patients with AQP4-IgG seropositive NMOSD. PRIMARY OBJECTIVES: I. To assess the safety of the tanCART-19/20 cells in treating NMOSD patients. II. Determine duration of in vivo survival of tanCART-19/20 cells. SECONDARY OBJECTIVES: I. To assess the efficacy of the tanCART-19/20 cells in treating NMOSD patients. II. The secondary outcome measures: annual relapse rate (ARR), Expanded Disability Status Scale Score(EDDS), Best Corrected Visual Acuity (Log MAR), Spectral-Domain Optical Coherence Tomography (SD-OCT), Flash Visual Evoked Potential (FVEP) and Immunological assessments. OUTLINE: Patients receive anti-CD19/20-CAR (coupled with CD137 and CD3 zeta signalling domains) vector-transduced autologous T cells on days 0 in the absence of unacceptable toxicity. The infusion dose is 1E5-2E6 CAR positive T cells/kg, and dose escalation methods obey the traditional 3+3 design (three doses groups: 1-2E5, 3-6E5, 1-2E6 CAR-T cells). After completion of study treatment, patients are followed intensively for 6 months, every 6 months for 2 years, and annually thereafter for 3 years.

Official Title
-----------------
Clinical Study of CD19/CD20 tanCAR T Cells in Relapsed and/or Refractory AQP4-IgG Seropositive Neuromyelitis Optica Spectrum Disorders (NMOSD)

Conditions
-----------------
Neuromyelitis Optica Spectrum Disorder

Intervention / Treatment
-----------------
* Biological: Corticosteroids & tanCART19/20


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinical diagnosis of neuromyelitis optica spectrum disorders (NMOSD) patients. Patients with AQP4-IgG seropositive by cell-based assay. Patients with corticosteroid treatment combined immunosuppressant (azathioprine or mycophenolate mofetil or rituximab) still recurrence. 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. Best corrected visual acuity(BCVA)<20/60. Normal bone marrow reserve function: neutrophils>1 500/mm3, Hemoglobin > 10g/dL, Platelet count > 100 000/mm3. Normal liver and kidney function: Creatinine < 2.5 mg/dl, ALT (alanine aminotransferase)/AST (aspartate aminotransferase) < 3x normal, Bilirubin < 2.0 mg/dl. Successful test expansion of tanCART19/20 cells. Adequate venous access for apheresis, and no other contraindications for leukapheresis. Voluntary informed consent is given. Exclusion Criteria: 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). 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). Concurrent use of systemic steroids or immunosuppressant in the last two weeks. Feasibility assessment during screening demonstrates < 30% transduction of target lymphocytes, or insufficient expansion (< 5-fold) in response to CD3/CD137 costimulation. Other patients who are not suitable for CAR-T therapy judged by the biotherapy physician.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Corticosteroids & tanCART19/20<br>Twelve days of high-dose IV methylprednisolone to reduce acute inflammation, then infuse anti-CD19/20-CAR retroviral vector-transduced autologous derived T cells only once. | Biological: Corticosteroids & tanCART19/20<br>* Twelve days of high-dose IV methylprednisolone (1000mg×3 days, 500mg×3 days, 240mg×3 days, 120mg×3 days) before anti-CD19/20 CAR T cells infusion. The dose is 1E5 2E6 anti-CD19/20-CAR positive T cells. The cells infusion process may last for 30 min.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of study related adverse events | defined as >= Grade 3 signs/symptoms, laboratory toxicities, and clinical events that are possibly, likely, or definitely related to study treatment. | From baseline to 12 months after | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized relapse rate (ARR) of NMOSD Attacks | Compare annualized relapse rate before and one year after initial CAR-T administration. | Baseline, 12 months | 
| Change in Expanded Disability Status Scale (EDDS) Score | The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death) in half-point increments. | Baseline, 12 months | 
| Change in Best Corrected Visual Acuity (Log MAR) | Visual acuity assessment through Snellen's test chart. | Baseline, 12 months | 
| Change in peripapillary retinal nerve fibre layer(pRNFL) | Compared pRNFL before and one year after initial CAR-T administration. | Baseline, 12 months | 
| Change in macular ganglion cell-inner plexiform layers (mGCIPL) | Compared mGCIPL before and one year after initial CAR-T administration. | Baseline, 12 months | 
| Change in Flash Visual Evoked Potential (FVEP) | Compared FVEP before and one year after initial CAR-T administration. | Baseline, 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neuromyelitis Optica Spectrum Disorder, aquaporin4-IgG, CAR-T therapy