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

NCT ID: NCT04561557

Last Updated: 2024-10-30

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-22
• Study Completion Date: 2027-05-31

Brief Summary

Antibody-mediated inflammatory diseases of the nervous system (also known as autoimmune diseases of the nervous system) are autoimmune diseases in which autoimmune cells and immune molecules attack the nervous system as the main pathogenic mechanism. In the immune response, pathogenic antibodies acting on autoantigens of the nervous system are collectively referred to as autoantibodies of the nervous system, and antibody-mediated inflammatory diseases of the nervous system can occur in the central nervous system, peripheral nervous system, and neuromuscular junctions, and muscles. In this study, we will recruit eight kinds of autoimmune diseases of nervous system including Neuromyelitis Optica Spectrum Disorder (NMOSD), Myasthenia Gravis (MG), Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), idiopathic inflammatory myopathyand (IIM), multiple sclerosis (MS), autoimmune encephalitis (AE), Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) and POEMS Syndrome. 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 neurological autoimmune diseases driven by abnormal antibody 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 antibody-mediated idiopathic inflammatory diseases.

Conditions

Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Neuromyelitis Optica Spectrum Disorder; Myasthenia Gravis; Chronic Inflammatory Demyelinating Polyradiculoneuropathy; Idiopathic Inflammatory Myopathies; Multiple Sclerosis; Autoimmune Encephalitis; Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD); POEMS Syndrome

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CAR T cells therapy，Dose level 1: 0.5 × 10^6 CAR-T cells/Kg

The tolerability and safety of CT103A cells will be assessed in an initial dose of 0.5×10^6 CAR-T cells/Kg and three subjects will be enrolled firstly. If no dose-limiting toxicity (DLT) occurs and at least one subject benefits from the treatment, there will be two options for the investigator based on the available data: 1) three more subjects will be enrolled in the 0.5 × 10^6 CAR-T cells/Kg group and DLT will be evaluated in a total of six subjects; 2) another three subjects will be treated with 1 × 10^6 CAR-T cells/Kg instead of 0.5 × 10^6 CAR-T cells/Kg.

If DLT occurs in one of the first three subjects, three more subjects will be enrolled in this cohort to reach the total subjects of six.

Group Type: EXPERIMENTAL

CT103A cells

Intervention Type: BIOLOGICAL

Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to manufacture CT103A cells, during which cyclophosphamide will be administered for the purpose of lymphocytes depletion. After lymphodepletion, subjects will receive one dose treatment with CT103A cells by intravenous (IV) infusion. The initial dose of 0.5×10\^6 CAR+ T cells/kg will be infused on day 0.

Cyclophosphamide and fludarabine

Intervention Type: DRUG

Subjects will receive one 3-day cycle of lymphodepletion starting 4 days prior to CT103A infusion on Day 0.

Subjects will be given IV infusion of cyclophosphamide 300 mg/m2/day on day -4, -3 and -2, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.

CAR T cells therapy，Dose level 2: 1 × 10^6 CAR-T cells/Kg

If neither DLT nor efficacy is shown in the first three subjects, the dose of CAR-T cells will be increased to 1 × 10\^6 CAR-T cells/kg to assess DLT.

Group Type: EXPERIMENTAL

CT103A cells

Intervention Type: BIOLOGICAL

Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to manufacture CT103A cells, during which cyclophosphamide will be administered for the purpose of lymphocytes depletion. After lymphodepletion, subjects will receive one dose treatment with CT103A cells by intravenous (IV) infusion. The initial dose of 0.5×10\^6 CAR+ T cells/kg will be infused on day 0.

Cyclophosphamide and fludarabine

Intervention Type: DRUG

Subjects will receive one 3-day cycle of lymphodepletion starting 4 days prior to CT103A infusion on Day 0.

Subjects will be given IV infusion of cyclophosphamide 300 mg/m2/day on day -4, -3 and -2, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.

CAR T cells therapy，Dose level 3: 0.25 × 10^6 CAR-T cells/Kg

If DLT occurs in two subjects, whether to test the safety and efficacy in 0.25 × 10\^6 CAR-T cells/kg group will be determined by the investigator based on the initial data of efficacy, PK and PD.

Group Type: EXPERIMENTAL

CT103A cells

Intervention Type: BIOLOGICAL

Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to manufacture CT103A cells, during which cyclophosphamide will be administered for the purpose of lymphocytes depletion. After lymphodepletion, subjects will receive one dose treatment with CT103A cells by intravenous (IV) infusion. The initial dose of 0.5×10\^6 CAR+ T cells/kg will be infused on day 0.

Cyclophosphamide and fludarabine

Intervention Type: DRUG

Subjects will receive one 3-day cycle of lymphodepletion starting 4 days prior to CT103A infusion on Day 0.

Subjects will be given IV infusion of cyclophosphamide 300 mg/m2/day on day -4, -3 and -2, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.

Interventions

CT103A cells

Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to manufacture CT103A cells, during which cyclophosphamide will be administered for the purpose of lymphocytes depletion. After lymphodepletion, subjects will receive one dose treatment with CT103A cells by intravenous (IV) infusion. The initial dose of 0.5×10\^6 CAR+ T cells/kg will be infused on day 0.

Intervention Type: BIOLOGICAL

Cyclophosphamide and fludarabine

Subjects will receive one 3-day cycle of lymphodepletion starting 4 days prior to CT103A infusion on Day 0.

Subjects will be given IV infusion of cyclophosphamide 300 mg/m2/day on day -4, -3 and -2, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Male or female subjects aged 18-75 years (including 18 and 75 years);

2. Subjects with Relapsing/refractory Antibody-mediated inflammatory diseases of the nervous system without effective treatment, including:

1. 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. Subjects with MG with positive abnormal antibody, MG-ADL total score ≥ 6 points, MGFA classification II-IV defined by 2020 MGFA diagnostic criteria and meet the following requirement: i. At least one kind of immunosuppressant for standardized treatment for more than 1 year, and have one of the following poor control conditions: 1) continuous inability to affect daily life; 2) Exacerbation of MG symptoms and/or crisis attacks still occur despite standard treatment; 3) Inability to tolerate immunosuppressive therapy ii. Requires plasma exchange or maintenance therapy with IV gamma globulin

3. Subjects with CIDP with positive abnormal antibodies, INCAT disability scale with total score of 2-9 defined by 2021 EAN/PNS diagnostic criteria and meet the following requirement: i. Standardized use of at least one first-line therapy for more than 3 months (cortisol hormone therapy, gamma globulin or plasma exchange therapy) with poorly-controlled symptoms. ii. Inability to tolerate cortisol hormones, gamma globulin, and plasmapheresis because of side effects or other conditions

4. Subjects were diagnosed with IIM defined by 2017 European League against Rheumatism/American Rheumatology (EULAR/ACR) conference Class criteria; At least one kind of cardiac enzymes (CK, AST, ALT, ALD, LDH) ≥1.5×ULN during the screening period, or Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) ≥6, or at least one other sign of active disease within the last 6 months: MRI, EMG, or muscle biopsy; positive serological tests for myositis-specific antibodies (MSA) or myositis-associated autoantibodies (MAA), or antinuclear antibody (ANA). and meet one of the following requirements:

i. After at least 1 month of corticosteroid therapy and standardized use of at least one immunosuppressant/modulator (eg, azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, Cyclophosphamide, leflunomide, intravenous gamma globulin, etc.) for more than 3 months with poorly-controlled symptoms.

ii. ii. Inability to tolerate the above traditional regimens due to side effects or other conditions;

e. Subjects were diagnosed with PMS (including PPMS and SPMS) or RMS according to the 2017 revision of the McDonald diagnostic criteria；EDSS score between 2 to 7 points inclusive, at screening. Subjects with RMS should meet one of the following requirements after standard therapy: i. at least two relapses in the last two years before screening. ii. at least one relapse in the last one year before screening. iii. positive Gd-enhancing MRI in the last one year before screening.

f. Subjects were diagnosed with POEMS syndrome according to the 2021 revised IMWG diagnostic criteria and meet all of the following requirements: i. bone marrow involvement; ii. no response to traditional regimens treatment including corticosteroid, chemotherapy, protease inhibitor or inability to tolerate the above traditional regimens; iii. Have measurable lesions (refer to the 2021 revised IMWG standard) iv. VEGF > 2 ULN; v. ECOG score ≥1; vi. ONLS score ≥1.

g. Subjects were diagnosed with autoimmune encephalitis according to the 2016 International Diagnostic Criteria for Autoimmune Encephalitis and meet all of the following requirements: i. at least one pathogenic antibody positive; ii. previously standardized use of corticosteroid, at least one immunosuppressant/modulator, including CD20 monoclonal antibody with poorly-controlled symptoms or intolerance; iii. onset of autoimmune encephalitis within 3 months prior to screening; iv. mRS Score ≥2 or CASE score ≥4.

h. Subjects were diagnosed with MOGAD according to the 2023 International MOGAD Diagnostic criteria and meet all of the following requirements: i. a documented positive serum MOG Ab test using a cell-based assay (CBA); ii mRS Score ≥2; iii previously standardized use of corticosteroid, at least one immunosuppressant/modulator, including CD20 monoclonal antibody with poorly-controlled symptoms or intolerance.

3. 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.

4. Enrolled subjects must have satisfactory organ function and laboratory findings as defined by the following:i. 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; ii. Liver function: total serum bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤ 1.5x the institutional normal upper limit (ULN); iii. Kidney function: CrCl ≥ 60 ml/min/1.73m2 (according to the following Cockcroft-Gault formula); iv. Electrolytes: blood potassium ≥ 3.0 mmol/L; blood calcium ≥ 2.0 mmol/L, blood magnesium ≥ 0.5 mmol/L; v. Coagulation function: fibrinogen ≥ 1.0 g/L; APTT ≤ ULN + 10s; PT ≤ ULN + 3s.

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

6. Echocardiography suggests LVEF≥ 50%.

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

8. 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).

9. 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. MG crisis was not effectively controlled within 2 weeks before enrollment.

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

10. 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.

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

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

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

14. Previous treatments: History of thymectomy within 12 months prior to CT103A infusion;

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

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 < 50 × 10^9/L;

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Nanjing IASO Biotechnology Co., Ltd.

INDUSTRY

Sponsor Role: collaborator

Tongji Hospital

OTHER

Sponsor Role: lead

Responsible Party

Wei Wang

Professor of Neurology, President of Tongji Hospital

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wei Wang, MD

Role: PRINCIPAL_INVESTIGATOR

Tongji Hospital

Locations

Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology

Wuhan, Hubei, China

Site Status: RECRUITING

Countries

China

Central Contacts

Chuan Qin, MD

Role: CONTACT

qinchuan712@126.com

86-27-83663337

Chuan Qin, MD

Role: CONTACT

chuanqin@tjh.tjmu.edu.cn

86-27-83663332

Facility Contacts

Chuan Qin, PhD

Role: primary

qinchuan712@126.com

86-27-83663337

Chuan Qin, MD

Role: backup

chuanqin@tjh.tjmu.edu.cn

86-27-83663333

References

Qin C, Dong MH, Zhou LQ, Chu YH, Pang XW, He JY, Shang K, Xiao J, Zhu L, Ye H, Cai SB, Wang D, Bu BT, Meyer Zu Horste G, Li CR, Tian DS, Wang W. Anti-BCMA CAR-T therapy in patients with progressive multiple sclerosis. Cell. 2025 Oct 15:S0092-8674(25)01088-8. doi: 10.1016/j.cell.2025.09.020. Online ahead of print.

Reference Type: DERIVED

PMID: 41101309 (View on PubMed)

Dong MH, Mei ZC, Zhou LQ, Heming M, Xu LL, Liu YX, Pang XW, Chu YH, Cai SB, Ye H, Shang K, Xiao J, Meyer Zu Horste G, Wang W, Qin C, Tian DS. Anti-BCMA CAR-T cell therapy in relapsed/refractory chronic inflammatory demyelinating polyneuropathy. Med. 2025 Sep 12;6(9):100704. doi: 10.1016/j.medj.2025.100704. Epub 2025 May 26.

Reference Type: DERIVED

PMID: 40425008 (View on PubMed)

Keam SJ. Equecabtagene Autoleucel: First Approval. Mol Diagn Ther. 2023 Nov;27(6):781-787. doi: 10.1007/s40291-023-00673-y. Epub 2023 Sep 2.

Reference Type: DERIVED

PMID: 37658205 (View on PubMed)

Other Identifiers

CARTinNS

Identifier Type: -

Identifier Source: org_study_id