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Cyclophosphamide

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Fludarabine phosphate

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Alkylating Agents

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.

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.

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.

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.

CT103A cells

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.

Cyclophosphamide and fludarabine

Chuan Qin, MD

Chuan Qin, PhD

Wei Wang, MD

Bitao Bu, MD

Min Zhang, MD

Daishi Tian, MD

Jianfeng Zhou, MD

Chunrui Li, MD

Di Wang, MD

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.

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

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

the number of attacks divided by observed year after CT103A cells infusion

the number of accumulate total active MRI lesions after CT103A infusion

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.

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.

Corrected visual acuity is determine by Snellen E chart held at a distance of 5 meters. Higher score indicates better vision.

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).

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

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.

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.

Including motor nerve distal latency, proximal latency, compound muscle motor potential (CMAP), motor nerve conduction velocity, sensory nerve conduction velocity, sural nerve potential

For MMT score, 16 muscle groups/ motions will be tested (not individual muscles). 14 of these are tested bilaterally.

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

Calculating the hyperintensity of muscle MRI T2/STIR sequence in patients with IMNM

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.

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.

usual visual analog scale (VAS) of pain is used to evaluate pain after CT103A infusion (line from 0: no pain to 10:worst pain)

The number of In-patient hospitalization is defined as a stay in hospital that goes beyond midnight of the first day of admission.

Changes of concentration( pg/mL) of cytokines ( such as ferritin, CRP, IL-6 and procalcitonin) will be analyzed after CT103A cells infusion.

Anti-drug antibodies (ADA) against CAR on CT103A cells will be analyzed after CT103A cells infusion.

Levels of replication competent lentivirus (RCL) will be monitored after CT103A cells infusion.

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.

Annualized relapse rate (ARR): Number of MS relapses divided by observed year after CT103A cells infusion

Time from CT103A infusion to the first relapse of MS

The changes of enhancing Lesions as detected by brain Magnetic Resonance Imaging (MRI)

Annualized rate of T2 lesions： Number of New, and/or Enlarging T2 Hyperintense Lesions as detected by MRI divided by observed year after CT103A cells infusion

The percent change of T2 lesions volume as detected by MRI from the baseline

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).

The no evidence of disease activity-3 (NEDA-3), defined as no relapse, no disability worsening, and no MRI activity

Time to onset of 3-month CDP as assessed by EDSS score

Time to onset of 6-month CDP as assessed by EDSS score

Including Fatigue Symptoms and Impacts Questionnaire -Relapsing Multiple Sclerosis (FSIQ-RMS), General Anxiety Disorder Scale (GAD-7), Patient Health Questionnaire (PHQ-9), Health Utilities Index (HUI-III), Multiple Sclerosis Impact Scale (MSIS-29).

Definition of Response:

1. There is a one-point improvement in ECOG performance score; and/or
2. ≥ 50% reduction in ONLS score.

Hematological response rate: Percentage of subjects who achieved partial response (PR) or better according to 2021 IMWG Uniform Response Criteria.

Definition of Neural Response: a) There is a one-point improvement in ONLS score; and/or b) ≥ 15% reduction in mNIS+7 score.

The changes of VEGF levels after CT103A cells infusion.

PET response rate: Percentage of subjects who achieved response according to 2021 IMWG Uniform Response Criteria.

Percentage of subjects who achieved response of other organs.

Time to ≥1point improvement in modified Rankin score (mRS) from baseline without rescue therapy.

Time to first relapse: Time from CT103A infusion to the first relapse of AE (days).

The time to seizure-free (Patients with autoimmune encephalitis have sympotmatic seizures in the acute phase) or the time from seizure-free (without rescue therapy) to rescue therapy.

The changes of Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score from baseline.

The changes of Montreal Cognitive Assessment Scale (MoCA) total scores from baseline.

The changes of Total Clinical Global Impressions (CGI) score from baseline.

The changes of Total Glasgow Coma Score (GCS) from baseline.

The changes of Total Minimum Mental State Examination Score (MMSE) from baseline.

The number of faciobrachial dystonic seizure (FBDS) in patients with LGI1 antibody-positive encephalitis.

Annualized recurrence rate: The number of MOGAD relapses divided by observed year after CT103A cells infusion

Time to first relapse: Time from CT103A infusion to the first relapse of MOGAD.

The changes of enhancing Lesions as detected by MRI.

To evaluate the DLT occurred within 3 months after CT103A infusion

To evaluate the AEs occurred within 2 years after CT103A infusion

The changes of concentration of soluble BCMA in the peripheral blood after CT103A infusion.

The changes of pathogenic antibody titers in peripheral blood or cerebrospinal fluid.

The changes of peripheral blood Neurofilament Light chain (NfL) concentration in patients with MS.

The number of BCMA CAR gene copies (VCN，copies/μg DNA) in peripheral blood and cerebrospinal fluid after administration.

The concentration of BCMA CAR T cells (cells/mL) in peripheral blood after administration was detected by flow cytometry.

Nanjing IASO Biotechnology Co., Ltd.

Tongji Hospital

Professor of Neurology, President of Tongji Hospital

Gland and Hormone Related Diseases

Glioma

Epilepsies, Partial

Epilepsy

Hashimoto Disease

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Thyroiditis

Thyroiditis, Autoimmune

Thyroid Diseases

Endocrine System Diseases

Lymphomatous Thyroiditis

Neuroepithelioma

Amino Acids

Leucine

Mei-Ping Ding

Chun-Hong Shen

Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis has been increasingly identified as the second most common type of autoimmune encephalitis after anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. It presents with acute or subacute onset of epileptic seizures, anterograde amnesia, behavior disturbances, sleep disorders and hyponatremia. In most patients with anti-LGI1 encephalitis, immunotherapy is successful in treating the encephalitis. However, relapses, chronic epilepsy, cognitive declines and psychiatric problems have been reported in some cases.

So far, prospective studies to evaluate its clinical outcomes still remain limited. In this project, the investigators will use clinical features and advanced paraclinical examinations to prospectively investigate the clinical outcomes and the associated factors in patients with anti-LGI1 encephalitis.

In this prospective study, the investigators are aiming to recruit newly diagnosed patients with anti-LGI1 encephalitis. At the acute stage and during the follow-up, some routine and advanced paraclinical examinations will be conducted, including dynamic blood and/or cerebrospinal fluid (CSF) test, multimodal brain magnetic resonance imaging (MRI) including functional MRI, diffusion tensor imaging, arterial spin labeling, et al), Electroencephalography (EEG) or continuous video-EEG (VEEG), positron emission tomography (PET), neuropsychological tests and some other paraclinical examinations. Through the comprehensive analysis, the clinical outcomes and associated factors are further explored in anti-LGI1 encephalitis.

Serum and cerebrospinal fluid samples will be stored to test antibodies, cytokines, immune cells and other relevant molecules. And patients have the right to destroy them at any time.

A Prospective Study to Evaluate Clinical Outcomes in Anti-LGI1 Encephalitis

A Prospective Study to Evaluate Clinical Outcomes in Patients With Anti-leucine-rich Glioma-inactivated 1 Encephalitis

The incidence of different seizure outcomes and associated factors will be analyzed.

modified Rankin scale, ranging from 0-6, higher scores mean a worse outcome

clinical assessment scale for autoimmune encephalitis, ranging from 0-27, higher scores mean a worse outcome

the Wechsler Memory Scale, high score means a good memory.

Rey Auditory Verbal Learning Test (RAVLT), high score means a good vebal episodic memory.

with 3T magnetic resonance imaging (MRI), volumes of the whole hippocampus, hippocampal subfields and other relevant regions were determined using FreeSurfer. The unit of volume is described as mm3.

Second Affiliated Hospital, School of Medicine, Zhejiang University

Heart and Blood Diseases

Mitral Valve Insufficiency

Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Autoantibodies

Children and young people (ages 8-24 years) with a diagnosis of NMDAR-antibody encephalitis.

Children and young people (ages 8-24 years) with a diagnosis of autoantibody-negative but probable autoimmune encephalitis or definite autoimmune limbic encephalitis.

Healthy children and young people (ages 8-24 years).

Not applicable - non-interventional study

Michael R Eyre, MBBS MRes

David W Carmichael, PhD MSci

Ming J Lim, MBBS PhD

Autoimmune encephalitis is brain inflammation caused by the immune system mistakenly reacting against proteins in the brain. The commonest form is called NMDAR-antibody encephalitis (N-methyl-D-aspartate receptor antibody encephalitis), a rare condition which mainly affects children and young people and causes difficulties in memory, thinking and mental health which can have significant long-term impacts on education, employment and quality of life.

In this project we will use advanced magnetic resonance imaging (MRI) to measure changes in the structure, function and chemistry of the brains of children and young people who are in early recovery from NMDAR-antibody encephalitis and other forms of immune-mediated encephalitis. We will investigate if MRI measurements in patients differ from those in healthy people, and if they can help predict patient outcome one year later, assessed by tests of memory, thinking, mental health and functioning in daily life.

This study aims to develop non-invasive, in vivo measures of neurobiological dysfunction derived from the overarching hypothesis that dysfunction of inhibitory interneurons alters the cerebral concentrations of gamma-aminobutyric acid (GABA) and glutamate (Glu) and underlies T2 changes and deficient connectivity in functional networks in early recovery from NMDAR-antibody encephalitis. Our ambition is to identify the best potential prognostic biomarkers from these neurometabolite measurements and structural and functional MRI.

Our primary objective is to test the following specific hypotheses in children and young people with NMDAR-antibody encephalitis:

* Hypothesis 1: GABA is decreased, and Glu increased, on MR spectroscopy of the medial temporal lobe and medial prefrontal cortex in NMDAR-antibody encephalitis.
* Hypothesis 2: Local GABA and Glu are correlated with (i) resting-state functional MRI (fMRI) based functional connectivity and (ii) parameter map-based microstructural changes. Specifically, we hypothesise that (i) GABA is positively correlated and Glu inversely correlated with functional connectivity, assessed by whole-brain mapping of the default mode network and seed-based analysis of hippocampal-frontal connectivity; and (ii) Glu is positively correlated and GABA inversely correlated with median T2 values within the hippocampus.
* Hypothesis 3: Local neurometabolites, network measures and microstructural changes predict cognitive, psychiatric and functional outcome at one year. Specifically, we hypothesise that medial temporal Glu, GABA and hippocampal T2 predict memory performance, and prefrontal Glu and GABA predict attention, executive function and fluid intelligence.

Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis

Consent will be requested from participants to share imaging data and summary clinical and demographic data. Where participants consent, imaging data will be de-identified, removing facial features from the magnetic resonance images and all identifying information will be removed from the image header (the part of the file that describes how the image data was acquired). The resulting data will be shared together with anonymised clinical data at the request of other researchers.

Measured with MR spectroscopy - stimulated echo acquisition mode (STEAM) sequence

Quantitative MRI parameter maps including measurement of median T2 values in the hippocampus

Whole-brain mapping of the default mode network and seed-based analysis of hippocampal-frontal connectivity

Cognitive test (higher score indicating better outcome)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy of CT103A Cells for Relapsed/Refractory Antibody-associated Inflammatory Diseases of the Nervous System	NCT04561557	Autoimmune Dise... Autoimmune Dise... Neuromyelitis O... Myasthenia Grav... Chronic Inflamm... Idiopathic Infl... Multiple Sclero... Autoimmune Ence... Myelin Oligoden... POEMS Syndrome	CT103A cells Cyclophosphamid...	18 Years - 75 Years	Tongji Hospital
A Prospective Study to Evaluate Clinical Outcomes in Anti-LGI1 Encephalitis	NCT06173076	Autoimmune Ence... Leucine-Rich Gl...		18 Years - 100 Years	Second Affiliated Hospital, School of Medicine, Zhejiang University
Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis	NCT05280600	Anti-N-Methyl-D... Autoimmune Ence...	Not applicable ...	8 Years - 24 Years	King's College London
New Biomarkers in Auto-immune Encephalitis and Neurological Paraneoplastic Syndromes	NCT05728931	Paraneoplastic ... Autoimmune Ence...	Test of biologi...	-	Hospices Civils de Lyon
Characterisation of Clinical Phenotypes and Outcomes of Ma2 Patient	NCT05645185	Autoimmune Ence... Paraneoplastic ...	Diagnosis test	18 Years -	Hospices Civils de Lyon
Autoimmune Encephalitis With Anti-NMDA Receptor Antibodies Following Herpetic Encephalitis	NCT04339127	Autoimmune Ence... Anti NMDA Recep... Herpetic Enceph...	Description and...	-	Hospices Civils de Lyon
Safety and Efficacy of CT103A Cells for Relapsed/Refractory Antibody-associated Inflammatory Diseases of the Nervous System	NCT04561557	Autoimmune Dise... Autoimmune Dise... Neuromyelitis O... Myasthenia Grav... Chronic Inflamm... Idiopathic Infl... Multiple Sclero... Autoimmune Ence... Myelin Oligoden... POEMS Syndrome	CT103A cells Cyclophosphamid...	18 Years - 75 Years	Tongji Hospital

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