Safety and Efficacy of CT103A Cells for Relapsed/Refractory Antibody-associated Idiopathic Inflammatory Diseases of the Nervous System

• Status: Recruiting
• Trial end date: 2023-12-31
• Target enrollment: 0
• Participant gender: All

Summary

Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disorder characterized by recurrent attacks of optic neuritis and myelitis. A strong humoral response with autoantibodies produced by plasma cells (effector B cells) against aquaporin-4 (AQP4) water channels on astrocytes has been identified as the main characteristic of NMOSD physiology. B-cell maturation antigen (BCMA) is expressed on the surface of plasma cells, thus making it an ideal target for targeted therapies. Chimeric antigen receptor (CAR) T cells against BCMA offers another potential therapeutic option to eliminate plasma cells in patients with AQP4-IgG-seropositive NMOSD who still suffer recurrent attacks from conventional treatments. In the current study, the safety and efficacy of a novel CAR-T cell therapy using CT103A cells, are evaluated in patients with relapsed/refractory NMOSD.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Tongji Hospital
• Collaborator: Nanjing IASO Biotherapeutics Co.,Ltd
• Treatments: Cyclophosphamide; Fludarabine

Criteria

Inclusion Criteria:

1. Subjects with relapsed/refractory NMOSD that previously met the diagnostic criteria of NMOSD by 2015 International Panel for NMO Diagnosis (IPND):

a. Subjects must be diagnosed as AQP4-IgG-positive NMOSD defined by 2015 criteria of IPND NMOSD and meet the following requirements: i. At least one kind of immunosuppressant has been used for more than one year with poorly-controlled symptoms; ii. Clinical evidence of at least two relapses in the last 12 months or three relapses in the last 24 months and one relapse in the preceding 12 months before screening.

2. All acute toxic reactions resolved to baseline or ≤ grade 1 assessed using NCI-CTCAE v5.0 except the ones adjudicated by the investigator to pose no risks on subjects.

3. Enrolled subjects must have satisfactory organ function and laboratory findings as defined by the following:

1. Blood tests: absolute neutrophil count ≥ 2×109/L (or normal lower limit set by the central lab of the institution), platelets ≥ 100 × 109/L, and hemoglobin ≥ 100 g/L;

2. Liver function: total serum bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤ 1.5x the institutional normal upper limit (ULN);

3. Kidney function: CrCl ≥ 60 ml/min/1.73m2 (according to the following Cockcroft-Gault formula);

4. Electrolytes: blood potassium ≥ 3.0 mmol/L; blood calcium ≥ 2.0 mmol/L, blood magnesium ≥ 0.5 mmol/L;

5. Coagulation function: fibrinogen ≥ 1.0 g/L; APTT ≤ ULN + 10s; PT ≤ ULN + 3s.

4. Blood oxygen saturation > 91% in resting state.

5. Echocardiography suggests LVEF≥ 50%.

6. Expected life expectancy ≥ 12 weeks as assessed by the investigator.

7. After signing the informed consent form, subjects and their partners must be willing to use effective and reliable method of contraception, devices or medicines, within one year after CT103A cells infusion (excluding contraception safety periods).

8. Subjects must provide written informed consent before the study begin.

Exclusion Criteria:

1. Patients do not have adequate mononuclear cells without mobilization for CAR-T cell manufacturing.

2. History of autoimmune hemolytic disease.

3. History of solid organ transplantation.

4. Patients were treated with alemtuzumab within 6 months prior to apheresis. Patients were treated with fludarabine or cladribine within 3 months prior to apheresis.

5. Patients with Papovaviruses infection.

6. Patients have been diagnosed with malignancies in the last 2 years prior to screening except for non-melanoma skin cancer, stage I cancers with complete resection and low risk of relapse, localized prostate cancer post-treatments, biopsy-confirmed in situ cervical cancer, or squamous epithelial lesion by PAP smear.

7. Chronic and active hepatitis B (HBV), hepatitis C (HCV), Human Immunodeficiency Virus (HIV) infection, CMV or syphilis infections concurrently.

8. Known history of primary immunodeficiency (innate or acquired).

9. Patients with severe impaired cardiac function, including but not limited to the following: unstable angina, myocardial infarction (within 6 months before enrollment), congestive heart failure (≥Grade III by NYHA), severe ventricular arrhythmia.

10. Cerebrovascular accidents, including transient ischemic attack or stroke history, occurred within 6 months before enrollment.

11. Major operation or surgical treatment caused by any reason within 4 weeks before enrollment.

12. Any serious and/or uncontrolled comorbidities which may interfere with the evaluation during the study in the opinion of the investigator

13. Previous treatments:

1. History of thymectomy within 12 months prior to CT103A infusion;

2. Corticosteroids (>20mg per day of prednisone or the equivalent) were used within 10 days before PBMC collection or 30 days before CT103A infusion; physiological replacement, topical use and local inhalers are allowed;

3. Immunosuppressants were used within 10 days before PBMC collection or 30 days before CT103A infusion;

4. Patients were treated with rituximab within 5 months before signing ICF signature;

5. Patients were treated with immunoglobin within 4 weeks before infusion;

6. Patients were treated with plasma exchange or double filtration within 4 weeks before infusion.

14. History of psychoactive drug abuse and failed to withdraw, or have a history of psychiatric disorders.

15. Habitual intake and incapable of withdrawal of grapefruit juice or overdose of tea, coffee and/or caffeinated drinks during the study.

16. Prone to allergies or history of serious allergy.

17. Pregnant or lactating women.

18. Patients with other conditions adjudicated by the investigator as unsuitable for enrollment.

Criteria for lymphodepletion and CAR-T cells infusion:

Before lymphocyte depletion and CAR-T cells infusion, patients are evaluated and those meeting the following criteria cannot be included:

1. Blood tests: neutrophil count < 2 × 109/L, platelet count < 100 × 109/L, or hemoglobin < 100 g/L (not applicable before infusion);

2. Oxygen inhalation is required to maintain blood oxygen saturation ≥ 91%;

3. Patients have the following conditions, including but not limited to: new arrhythmia cannot be controlled by drugs; hypotension requiring pressor drugs; bacterial, fungal or viral infection requiring intravenous antibiotic treatment; creatinine clearance rate < 50 ml/min ;

4. Patients require maintenance support treatment within one week to meet the criteria for lymphodepletion or CAR T cell infusion.

5. Cell infusion is delayed > 7 days after lymphodepletion for any reason;

6. Patients with other conditions adjudicated by the investigator as unsuitable for lymphodepletion or cell infusion.