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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

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Recurrence

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

NYESO-1 TCR-T cell are prepared via lentiviral infection. DLT was administered in a dose escalation test according to the 3 + 3 design. Seven days prior to infusion of TCR-T cell, subjects receive cytoreductive chemotherapy with Cyclophosphamide (250-500mg/m2/day) and Fludarabine (25mg/m2/day) for 3 days.

A single dose of Anti-NY-ESO-1 TCR transduced T cells (about 5×109) will be intravenously (i.v.) administered Additionally, following infusion of Anti-NY-ESO-1 TCR transduced T cells, IL-2 subcutaneous injections (500,000 IU/day) will be administered for 14 days concomitantly to each subject.

Seven days prior to infusion of TCR-T cell, subjects receive cytoreductive chemotherapy with cyclophosphamide (250-500mg/m2/day) plus fludarabine (25mg/m2/day) for 3 days.

Cyclophosphamide and Fludarabine

A single dose of Anti-NY-ESO-1 TCR transduced T cells (about 5×109) will be intravenously (i.v.) administered Additionally, following infusion of Anti-NY-ESO-1 TCR transduced T cells, IL-2 subcutaneous injections (500,000 IU/day) will be administered for 14 days concomitantly to each subject.

Anti-NY-ESO-1 TCR transduced T cells

Shiyue Li, MD

Chengzhi Zhou, MD

TCR-T cell therapy experienced a breakthrough for treating tumors in recent years. Phase I / II trial of NY-ESO-1-specific TCR-T treatment for synovial sarcoma and melanoma conducted by the Rosenberg team at the National Cancer Institute showed that 61% Synovial cell sarcoma and 55% melanoma had therapeutic responses. Another report of a phase I / II clinical trial for multiple myeloma showed that 20 patients received high affinity anti-NY-ESO-1 and LAGE-1 specific TCR-T treatment, 16 of them (80%) had the average progression-free survival of 19.1 months with minor side effect. These achievements indicate that TCR-T cell therapy can target a variety of tumors including solid tumors without any severe side effects found in CAR-T trials.

This study is mainly focused on tumor testis antigen (Cancer-Testis Antigen), because it is not expressed in normal cells. NY-ESO-1 antigen is commonly expressed in 10-50% of melanoma, lung, liver, esophageal, breast, prostate, bladder, thyroid and ovarian cancer cases, 60% of multiple myeloma cases, and 70-80% of synovial cell sarcoma. Approximately 700,000 new cases of lung cancer are identified each year in China, 70% of them die within one to two years after diagnosis due to the lack of effective treatment. To address that unmet needs, our TCR-T treatment targets non-small cell lung cancer with NY-ESO-1 antigen expression.

This study will investigate the safety and tolerability of TAEST16001 (TAEST: TCR Affinity Enhancing Specific T cell Therapy, autologous T cells transduced with affinity enhanced NY-ESO-1 TCR) cell therapy in subjects with NSCLC who have received prior therapy for their disease but their disease has progressed or relapsed.

This Phase 1 study is designed as a cell dose escalation trial evaluating the safety of TAEST16001 T cell therapy in subjects with NSCLC who have received prior therapy for their disease but the disease has progressed or relapsed. Anti-tumor activity and other exploratory objectives will be assessed. Subjects enter from a Screening Protocol and are positive for HLA-A2\*02:01 and have tumor that express NY-ESO-1. The subjects will be evaluated DLT and MTD using a modified 3+3 cell dose escalation design to determine the cell dose range. Subjects will receive cytoreductive chemotherapy with cyclophosphamide (250-500mg/m2/day) plus fludarabine (25mg/m2/day) on day -7 to day -5 followed by infusion of dose of about 5×109 TAEST16001 and IL-2(s.c.).

Subjects will stay in hospital for safety and efficacy assessment daily from T cell infusion (Day 0) through Day 7, and then weekly until week 4 and then at 8 weeks, 12 weeks, 16 weeks and every 3 months until progression of their disease.

One arm, open label, dose escalation, single dose phase I study of safety and tolerability.

NYESO-1 TCR-T cell are prepared via lentiviral infection. DLT was administered in a dose escalation test according to the 3 + 3 design. Seven days prior to infusion of TCR-T cell, subjects receive cytoreductive chemotherapy with cyclophosphamide (250-500mg/m2/day) plus fludarabine (25mg/m2/day) for 3 days.

Patients, who receive an infusion of TAEST16001, will remain in the hospital to be monitored for adverse events until they have recovered from the treatment.

Patients will have frequent follow-up visit to monitor the persistence of modified T cells and efficacy of the treatment.

NY-ESO-1 TCR （TAEST16001）for Patients With Advanced NSCLC

Pilot Study of Affinity-enhanced Anti-NY-ESO-1 TCR Engineered Autologous T Cells in NSCLC Patients

To evaluate the safety and feasibility of the administration of anti-NY-ESO-1 TCR transduced T cells in patients with HLA-A2+ NY-ESO-1 expressing NSCLC.

To evaluate the efficacy of NYESO-1 positive NSCLS patients treated with NY-ESO-1 antigen specific affinity-enhanced TCR transduced autologous T cell therapy.

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
NY-ESO-1 TCR （TAEST16001）for Patients With Advanced NSCLC	NCT03029273	Lung Cancer, No...	Cyclophosphamid... Anti-NY-ESO-1 T...	18 Years - 75 Years	Guangzhou Institute of Respiratory Disease
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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