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.
Eligibility criteria
This trial does not accept healthy volunteers
Qualifiers
Male or female subjects aged 18-75 years (including 18 and 75 years);
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 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
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
Disqualifiers
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.
Trial design
Design model
Sequential
Treatments tested in this trial
CT103A cells
Biological/Vaccine
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
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.
Treatment groups
36 Participants
are divided into 3 treatment groups
Group A: CAR T cells therapy，Dose level 1: 0.5 × 10^6 CAR-T cells/KgExperimental treatment 2 interventions
Group B: CAR T cells therapy，Dose level 2: 1 × 10^6 CAR-T cells/KgExperimental treatment 2 interventions
Group C: CAR T cells therapy，Dose level 3: 0.25 × 10^6 CAR-T cells/KgExperimental treatment 2 interventions
Trial outcomes
Primary outcomes
1
Types and incidence of dose-limiting toxicity (DLT) after CT103A cells infusion
To evaluate the DLT occurred within 28 days after CT103A infusion
Time frame
Up to 28 days post CT103A infusion
2
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
Time frame
Up to 2 years post CT103A infusion
Secondary outcomes
1
PD-Soluble BCMA
The changes of concentration of soluble BCMA in the peripheral blood after CT103A infusion.
Time frame
Up to 2 years post CT103A infusion
2
PD-Pathogenic antibody
The changes of pathogenic antibody titers in peripheral blood or cerebrospinal fluid.
Time frame
Up to 2 years post CT103A infusion
3
PD-Nfl（MS）
The changes of peripheral blood Neurofilament Light chain (NfL) concentration in patients with MS.
Time frame
Up to 2 years post CT103A infusion
4
PK-VCN
The number of BCMA CAR gene copies (VCN，copies/μg DNA) in peripheral blood and cerebrospinal fluid after administration.
Time frame
Up to 15 years post CT103A infusion
Other outcomes
1
NMOSD: Annualized relapse rate (ARR)
the number of attacks divided by observed year after CT103A cells infusion
Time frame
Up to 2 years post CT103A infusion
2
NMOSD: Accumulated total active MRI lesions
the number of accumulate total active MRI lesions after CT103A infusion
Time frame
Up to 2 years post CT103A infusion
3
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.
Time frame
Up to 2 years post CT103A infusion
4
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.
Time frame
Up to 2 years post CT103A infusion
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