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

NCT03605238 | Withdrawn Phase 1

• 1 other identifier: CHN-PLAGH-NO-S2018-002-02
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Neuromyelitis Optica Spectrum Disorder

Keywords

Neuromyelitis Optica Spectrum Disorder; aquaporin4-IgG; CAR-T therapy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Annualized relapse rate (ARR) of NMOSD Attacks

  Baseline, 12 months

• Change in Expanded Disability Status Scale (EDDS) Score

  Baseline, 12 months

• Change in Best Corrected Visual Acuity (Log MAR)

  Baseline, 12 months

• Change in peripapillary retinal nerve fibre layer(pRNFL)

  Baseline, 12 months

• Change in macular ganglion cell-inner plexiform layers (mGCIPL)

  Baseline, 12 months

Other Outcomes (5)

• in vivo existence of tanCART19/20

  Baseline, 12 months

• Determination of serum immunoglobulins

  Baseline, 12 months

• Determination of serum AQP4 antibodies

  Baseline, 12 months

Study Arms (1)

Corticosteroids & tanCART19/20

EXPERIMENTAL

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

Interventions

Corticosteroids & tanCART19/20 BIOLOGICAL

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.

Corticosteroids & tanCART19/20

Eligibility Criteria

• Age: 12 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Chinese PLA General Hospital: lead

Study Sites (1)

People's Liberation of Army General Hospital (PLAGH)

Beijing, Beijing Municipality, 100853, China

Location

MeSH Terms

Conditions

Neuromyelitis Optica

Interventions

Adrenal Cortex Hormones

Condition Hierarchy (Ancestors)

Myelitis, Transverse; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Optic Neuritis; Optic Nerve Diseases; Cranial Nerve Diseases; Demyelinating Diseases; Eye Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Quangang Xu, PhD

  Chinese PLA General Hospital

  STUDY DIRECTOR

• Huanfen Zhou, PhD

  Chinese PLA General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neuro-Ophthalmology

Study Record Dates

• First Submitted: June 29, 2018
• First Posted: July 30, 2018
• Study Start: August 15, 2018
• Primary Completion: August 15, 2019
• Study Completion: August 15, 2020
• Last Updated: September 19, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)