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

An Open Label Clinical Trial to Evaluate the Safety and Efficacy of CT103A Cells for the Treatment of Relapsed/Refractory Antibody-associated Idiopathic Inflammatory Diseases of the Nervous System

Antibody-mediated idiopathic 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 idiopathic 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 three kinds of autoimmune diseases of nervous system including Neuromyelitis Optica Spectrum Disorder (NMOSD), Myasthenia Gravis (MG), Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and Immune-Mediated Necrotizing Myopathy (IMNM). 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.

Study Overview

• Status: Recruiting
• Conditions: Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Myasthenia Gravis; Neuromyelitis Optica Spectrum Disorder; Chronic Inflammatory Demyelinating Polyradiculoneuropathy; Immune-Mediated Necrotizing Myopathy
• Intervention / Treatment: Biological: CT103A cells; Drug: Cyclophosphamide and fludarabine

• Study Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Chuan Qin, MD; Phone Number: 86-27-83663337; Email: qinchuan712@126.com
• Study Contact Backup: Name: Chuan Qin, MD; Phone Number: 86-27-83663332; Email: chuanqin@tjh.tjmu.edu.cn

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430000
      • Recruiting
      • Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology
      • Contact: Chuan Qin, PhD; Phone Number: 86-27-83663337; Email: qinchuan712@126.com
      • Contact: Chuan Qin, MD; Phone Number: 86-27-83663333; Email: chuanqin@tjh.tjmu.edu.cn
      • Principal Investigator: Wei Wang, MD
      • Sub-Investigator: Bitao Bu, MD
      • Sub-Investigator: Daishi Tian, MD
      • Sub-Investigator: Chuan Qin, MD
      • Sub-Investigator: Jianfeng Zhou, MD
      • Sub-Investigator: Chunrui Li, MD
      • Sub-Investigator: Di Wang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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. Subjects with MG with positive abnormal antibody, MG-ADL total score ≥ 6 points, MGFA classification II-IV defined by 2013 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 2010 EFNS/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 with IMNM with positive SRP or HMGCR antibody, have at least one proximal limb muscle strength less than grade 4 and elevated creatine kinase defined by 2016 ENMC diagnostic criteria and meet the following requirement:

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

5. 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.

6. 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.

7. Blood oxygen saturation > 91% in resting state.
8. Echocardiography suggests LVEF≥ 50%.
9. Expected life expectancy ≥ 12 weeks as assessed by the investigator.
10. 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).
11. 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 < 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Biological: 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 0.5×106 CAR+ T cells/kg will be infused on day 0.; Drug: 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 500 mg/m2/day on day -4, -3 and -2, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.
Experimental: 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 × 106 CAR-T cells/kg to assess DLT.	Biological: 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 0.5×106 CAR+ T cells/kg will be infused on day 0.; Drug: 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 500 mg/m2/day on day -4, -3 and -2, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.
Experimental: 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.	Biological: 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 0.5×106 CAR+ T cells/kg will be infused on day 0.; Drug: 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 500 mg/m2/day on day -4, -3 and -2, and fludarabine 30 mg/m2 over 30 minutes administered immediately after cyclophosphamide.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Types and incidence of dose-limiting toxicity (DLT) after CT103A cells infusion	To evaluate the DLT occurred within 3 months after CT103A infusion	3 months after CT103A cells infusion
Incidence and severity of AEs, including changes in vital signs, physical examination, laboratory parameters, Electrocardiograms and Echocardiograms.	To evaluate the AEs occurred within 2 years after CT103A infusion	2 years after CT103A cells infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NMOSD: Decrease of concentration of AQP4-IgG titers in the serum after CT103A infusion	the decrease of concentration of AQP4-IgG titers in serum after CT103A infusion will be compared with baseline	2 years after CT103A cells infusion
MG: Decrease of concentration of related abnormal antibody titers in the serum after CT103A infusion	the decrease of concentration of related abnormal antibody titers in serum after CT103A infusion will be compared with baseline	2 years after CT103A cells infusion
CIDP: Decrease of concentration of related abnormal antibody titers in the serum after CT103A infusion	the decrease of concentration of related abnormal antibody titers in serum after CT103A infusion will be compared with baseline	2 years after CT103A cells infusion
IMNM: Decrease of concentration of related abnormal antibody titers in the serum after CT103A infusion	the decrease of concentration of related abnormal antibody titers in serum after CT103A infusion will be compared with baseline	2 years after CT103A cells infusion
Absolute and relative levels of B cells and their subsets	Absolute and relative levels of B cells and their subsets	2 years after CT103A cells infusion
CT103A cells proliferation in patients with relapse/refractory NMOSD	Copy number of CT103A detected by PCR and concentration of CT103A detected by flow cytometry in peripheral blood will be analyzed.	2 years after CT103A cells infusion
Copy number of BCMA CAR gene in patients with relapse/refractory NMOSD	The copy number of BCMA CAR gene in peripheral blood after administration	2 years after CT103A cells infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of soluble BCMA in peripheral blood after CT103A cells	the changes of concentration of soluble BCMA in the peripheral blood after CT103A infusion.	2 years after CT103A cells infusion
NMOSD: Concentration of AQP4-IgG titers in the serum after CT103A infusion	Changes of concentration of AQP4-IgG titers in the serum after CT103A	2 years after CT103A cells infusion
NMOSD: Time to first relapse (day) of NMOSD after CT103A cells infusion	Time from CT103A infusion to the first relapse of NMOSD	2 years after CT103A cells infusion
NMOSD: Annualized relapse rate (ARR)	the number of attacks divided by observed year after CT103A cells infusion	2 years after CT103A cells infusion
NMOSD: Accumulated total active MRI lesions	the number of accumulate total active MRI lesions after CT103A infusion	2 years after CT103A cells infusion
NMOSD: Expanded Disability Status Scale (EDSS) score	EDSS and its associated functional system (FS) score provide a system for quantifying disability and monitoring changes in the level of disability over time. EDSS is a scale for assessing neurologic impairment in multiple sclerosis (MS). It consists of 7 FS (visual FS, brainstem FS, pyramidal FS, cerebellar FS, sensory FS, bowel and bladder FS, and cerebral FS) which are used to derive EDSS score ranging from 0 (normal neurological exam) to 10 (death from MS). A negative change from baseline indicates improvement. A participant was considered to have a worsening in overall EDSS score of at least 2 if baseline EDSS score was 0, or at least 1 point if baseline EDSS score is 1 to 5, or at least 0.5 point if baseline EDSS score is 5.5 or more.	2 years after CT103A cells infusion
NMOSD: Modified Rankin Scale	Modified Rankin Scale (mRS) is a profoundly valid and reliable measure of disability and is broadly utilized for assessing stroke outcomes and degree of disability. We characterized a favorable outcome as mRS ranging from zero up to two, while unfavorable outcome ranging for 3 up to 6.	2 years after CT103A cells infusion
NMOSD: Visual acuity	Corrected visual acuity is determine by Snellen E chart held at a distance of 5 meters. Higher score indicates better vision.	2 years after CT103A cells infusion
MG: Quantitative Myasthenia Gravis Score (QMG)	The QMG score is a 13-item scale used to quantify disease severity in myasthenia gravis. The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits).	2 years after CT103A cells infusion
MG: Myasthenia Gravis Activities if Daily Living (MG-ADL) Score	The MG-ADL is an eight-question survey of symptom severity, with each response graded from 0 (normal) to 3 (most severe). Two questions concern ocular, three oropharyngeal, one respiratory, and two extremity functions. Cumulative MG-ADL scores range from 0 to 24	2 years after CT103A cells infusion
CIDP: Inflammatory Neuropathy Cause and Treatment (INCAT) Score	The INCAT score comprises two parts, the arm score and the leg score. Based on a patient's level of impairment in their arms and legs, each part is scored between 0 and 5 points, resulting in an INCAT total score between 0 and 10.	2 years after CT103A cells infusion
CIDP: Medical Research Council (MRC) muscle function Score	The MRC score system for testing and grading of muscle function aims to provide a standardized and objective way to assess muscle function. It ranges from 0 to 5.	2 years after CT103A cells infusion
CIDP: Assess changes in nerve conduction test results	Including motor nerve distal latency, proximal latency, compound muscle motor potential (CMAP), motor nerve conduction velocity, sensory nerve conduction velocity, sural nerve potential	2 years after CT103A cells infusion
IMNM: Manual Muscle Testing (MMT) Score	For MMT score, 16 muscle groups/ motions will be tested (not individual muscles). 14 of these are tested bilaterally.	2 years after CT103A cells infusion
IMNM: Assess the changes in serum creatine kinase levels in patients with IMNM before and after treatment.	If the creatine kinase level drops to twice the upper limit of normal or below, it is defined as effective, and the effective rate is calculated	2 years after CT103A cells infusion
IMNM: Muscle MRI	Calculating the hyperintensity of muscle MRI T2/STIR sequence in patients with IMNM	2 years after CT103A cells infusion
36-item Short Form Generic Health Survey (SF-36) score	SF-36 will used to understand the health related quality-of -life of the subjects after CT103A infusion. The eight health concepts: limitations in physical activities because of health problems; limitations in social activities because of physical or emotional problems; limitations in usual role activities because of physical health problems; bodily pain; general mental health (psychological distress and well-being); limitations in usual role activities because of emotional problems; vitality (energy and fatigue); and general health perceptions will be searched. These outcomes will be grouped as physical component summary and mental component summary. The norm data is 0-100, the health related quality of life is increases as the scores are increased. The average score is 50.	2 years after CT103A cells infusion
EuroQol-five dimensions (EQ-SD) score	Health status is measured with the EuroQuality of Life Five Dimensions (EQ-5D) after CT103A infusion, which includes five dimensions and is used to evaluate the quality of life of sepsis survivors. They are mobility, self-care, usual activities, discomfort or pain and depression or anxiety. Levels are coded 1-5 and a total score is then generated. Results for the demographic measured will be displayed as a percentage value.	2 years after CT103A cells infusion
Visual analogue scale (VAS) pain score	usual visual analog scale (VAS) of pain is used to evaluate pain after CT103A infusion (line from 0: no pain to 10:worst pain)	2 years after CT103A cells infusion
Annual hospitalization rates	The number of In-patient hospitalization is defined as a stay in hospital that goes beyond midnight of the first day of admission.	2 years after CT103A cells infusion
Cytokines release after CT103A infusion	Changes of concentration( pg/mL) of cytokines ( such as ferritin, CRP, IL-6 and procalcitonin) will be analyzed after CT103A cells infusion.	2 years after CT103A cells infusion
Immunogenicity of CT103A cells	Anti-drug antibodies (ADA) against CAR on CT103A cells will be analyzed after CT103A cells infusion.	2 years after CT103A cells infusion
Detection of RCL	Levels of replication competent lentivirus (RCL) will be monitored after CT103A cells infusion.	2 years or until CAR is undetectable after CT103A cells infusion
Profiling of cell subtypes	Changes in cells in infused CAR T products, blood and CSF (including proportion of CD3+ T cells, CD3+CD4+ T cells and CD3+CD8+ T cells, ratio of CD4+ T/CD8+T, and single-cell sequencing) will be analyzed after CT103A cells infusion.	2 years after CT103A cells infusion

Collaborators and Investigators

• Sponsor: Tongji Hospital
• Collaborators: Nanjing IASO Biotherapeutics Co.,Ltd
• Investigators: Principal Investigator: Wei Wang, MD, Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 22, 2020
• Primary Completion (Anticipated): February 22, 2024
• Study Completion (Anticipated): May 31, 2024

Study Registration Dates

• First Submitted: September 10, 2020
• First Submitted That Met QC Criteria: September 18, 2020
• First Posted (Actual): September 23, 2020

Study Record Updates

• Last Update Posted (Actual): April 12, 2023
• Last Update Submitted That Met QC Criteria: April 10, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Adoptive T Cell Therapy; Chimeric antigen receptor; B-cell maturation antigen (BCMA); Autoimmune Diseases of the Nervous System
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms; Demyelinating Autoimmune Diseases, CNS; Demyelinating Diseases; Neoplasms by Site; Eye Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Nervous System Neoplasms; Optic Nerve Diseases; Cranial Nerve Diseases; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuromuscular Junction Diseases; Myelitis, Transverse; Optic Neuritis; Polyneuropathies; Nervous System Diseases; Myasthenia Gravis; Neuromyelitis Optica; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Polyradiculoneuropathy; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: CARTinNS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No