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

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

Official Title
-----------------
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

Conditions
-----------------
Autoimmune Diseases, Autoimmune Diseases of the Nervous System, Neuromyelitis Optica Spectrum Disorder, Myasthenia Gravis, Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Immune-Mediated Necrotizing Myopathy

Intervention / Treatment
-----------------
* Biological: CT103A cells
* Drug: Cyclophosphamide and fludarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. 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 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 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 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. 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. Blood oxygen saturation > 91% in resting state. Echocardiography suggests LVEF≥ 50%. Expected life expectancy ≥ 12 weeks as assessed by the investigator. 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). Subjects must provide written informed consent before the study begin. Exclusion Criteria: Patients do not have adequate mononuclear cells without mobilization for CAR-T cell manufacturing. History of autoimmune hemolytic disease. History of solid organ transplantation. Patients were treated with alemtuzumab within 6 months prior to apheresis. Patients were treated with fludarabine or cladribine within 3 months prior to apheresis. Patients with Papovaviruses infection. 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. Chronic and active hepatitis B (HBV), hepatitis C (HCV), Human Immunodeficiency Virus (HIV) infection, CMV or syphilis infections concurrently. MG crisis was not effectively controlled within 2 weeks before enrollment. Known history of primary immunodeficiency (innate or acquired). 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. Cerebrovascular accidents, including transient ischemic attack or stroke history, occurred within 6 months before enrollment. Major operation or surgical treatment caused by any reason within 4 weeks before enrollment. Any serious and/or uncontrolled comorbidities which may interfere with the evaluation during the study in the opinion of the investigator Previous treatments: History of thymectomy within 12 months prior to CT103A infusion; History of psychoactive drug abuse and failed to withdraw, or have a history of psychiatric disorders. Prone to allergies or history of serious allergy. Pregnant or lactating women. 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: Blood tests: neutrophil count < 2 × 109/L, platelet count < 100 × 109/L, or hemoglobin < 100 g/L (not applicable before infusion); Oxygen inhalation is required to maintain blood oxygen saturation ≥ 91%; 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 ; Patients require maintenance support treatment within one week to meet the criteria for lymphodepletion or CAR T cell infusion. Cell infusion is delayed > 7 days after lymphodepletion for any reason; Patients with other conditions adjudicated by the investigator as unsuitable for lymphodepletion or cell infusion.

Ages Eligible for Study
-----------------
Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR T cells therapy，Dose level 1: 0.5 × 10^6 CAR-T cells/Kg<br>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<br>* 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.<br>Drug: Cyclophosphamide and fludarabine<br>* 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.<br>|
| Experimental: CAR T cells therapy，Dose level 2: 1 × 10^6 CAR-T cells/Kg<br>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<br>* 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.<br>Drug: Cyclophosphamide and fludarabine<br>* 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.<br>|
| Experimental: CAR T cells therapy，Dose level 3: 0.25 × 10^6 CAR-T cells/Kg<br>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<br>* 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.<br>Drug: Cyclophosphamide and fludarabine<br>* 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.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Adoptive T Cell Therapy, Chimeric antigen receptor, B-cell maturation antigen (BCMA), Autoimmune Diseases of the Nervous System