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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

Plasmacytoma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Anticoagulants

Dermatologic Agents

Anti-Infective Agents

Other Dietary Supplements

Amino Acids

Dexamethasone

Lenalidomide

Dexamethasone acetate

BB 1101

Citric Acid

Sodium Citrate

Ichthammol

Ixazomib

Glycine

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

HIV Protease Inhibitors

Protease Inhibitors

Enzyme Inhibitors

Angiogenesis Inhibitors

Growth Inhibitors

Neurotransmitter Agents

Citrate

Patients receive ixazomib citrate PO on days 1, 8, and 15, lenalidomide PO QD on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo standard of care ASCT after completing 3 cycles of treatment.

Patients receive ixazomib citrate PO, lenalidomide PO QD, and dexamethasone PO as in Group I. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity.

Ixazomib Citrate

Questionnaire Administration

Angela Dispenzieri, M.D.

This phase II trial studies how well ixazomib citrate, lenalidomide, and dexamethasone work in treating patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Anti-inflammatory drugs, such as dexamethasone lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Giving ixazomib citrate, lenalidomide, and dexamethasone may work better in treating patients with POEMS syndrome.

PRIMARY OBJECTIVE:

I. Normalization of VEGF after 3 cycles of therapy.

SECONDARY OBJECTIVES:

I. Toxicity and safety of the combination of ixazomib citrate (ixazomib), lenalidomide, and dexamethasone.

II. Hematologic response after 3 cycles of therapy. III. Hematologic response rates and/or VEGF response at 12 months. IV. Overall survival.

EXPLORATORY OBJECTIVES:

I. Improvement of peripheral neuropathy (Overall Neuropathy Limitations Scale \[ONLS\], Modified Neurological Impairment Score for POEMS \[mNIS+7POEMS\], and performance score), ascites/effusions, diffusing capacity of the lungs for carbon monoxide (DLCO) after 3 cycles of therapy.

II. Improvement of peripheral neuropathy (ONLS, mNIS+7POEMS, and performance score), ascites/effusions, DLCO, and positron emission tomography (PET)-scan (if abnormal at baseline) at 12 months (both groups) and at 24 and 36 months (group 2 only).

III. Time to VEGF response, hematologic response, and clinical response. IV. Time to VEGF progression, hematologic progression, and clinical progression.

V. Doses delivered will be tabulated to establish tolerance of study drugs.

CORRELATIVE RESEARCH OBJECTIVES:

I. To describe changes in bone biomarkers with treatment of ixazomib, lenalidomide, and dexamethasone.

OUTLINE: Patients are assigned to 1 of 2 groups.

GROUP I: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15, lenalidomide PO once daily (QD) on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo standard of care autologous stem cell transplant (ASCT) after completing 3 cycles of treatment.

GROUP II: Patients receive ixazomib citrate PO, lenalidomide PO QD, and dexamethasone PO as in Group I. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months until disease progression and then every 6 months for up to 36 months.

Ixazomib Citrate, Lenalidomide, and Dexamethasone in Treating Patients With POEMS Syndrome

Ixazomib, Lenalidomide, and Dexamethasone for Patients With POEMS Syndrome

Improvement of peripheral neuropathy (Modified Neurological Impairment Score +7 polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) will be defined as decrease of \>= 2 points. Other neurologic tests including Overall Neuropathy Limitations Scale, polyneuropathy disability score, and EQ-5D-5L health questionnaire will be analyzed descriptively.

Improvements will be assessed by evaluating changes from baseline and will be described descriptively.

Median and range will be calculated for time to response in responding patients.

The distribution of time to progression will be estimated using the method of Kaplan-Meier.

Doses delivered will be tabulated to establish tolerance of drugs. Reasons for dose adjustments will be evaluated. Dose levels by cycle and total dose will be evaluated and summarized using descriptive statistics (median, range).

In each group, the rate of normalization of VEGF by 3 months (post-3 cycles) will be examined along with the prognostic factors for patients accrued to this study. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent binomial confidence intervals for the true success proportion will be calculated.

Hematologic response rate after 3 cycles of therapy (or 3 months after registration) will be estimated by the number of hematologic responses (partial response, very good partial response, or complete response) observed within 3 months of registration divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true hematologic response rate after 3 cycles of therapy (or 3 months after registration) will be calculated.

Hematologic response rate after 13 cycles of therapy (or 12 months) will be evaluated. Exact binomial 95% confidence intervals for the true rates at 12 months will be calculated.

Normalization of VEGF after 13 cycles of therapy (or 12 months after registration) will be evaluated. Exact binomial 95% confidence intervals for the true rates at 12 months will be calculated.

The distribution of survival time will be estimated using the method of Kaplan-Meier.

The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

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
Ixazomib Citrate, Lenalidomide, and Dexamethasone in Treating Patients With POEMS Syndrome	NCT02921893	Plasmacytoma POEMS Syndrome	Dexamethasone Ixazomib Citrat... Lenalidomide Questionnaire A...	18 Years -	Mayo Clinic
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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