Safety and Pharmacodynamics of QH103 Cell Injection in the Treatment of Patients With Relapsed/Refractory Antibody-Mediated Neurological Autoimmune Diseases.

Официальное название

An Open-Label Clinical Study to Evaluate the Safety and Pharmacodynamics of QH103 Cell Injection in the Treatment of Patients With Relapsed/Refractory Antibody-Mediated Neurological Autoimmune Diseases.

Обзор

This study is an open-label, exploratory, prospective clinical trial with dose escalation(according to "3+3" design), to evaluate the safety and tolerability of QH103(Universal CD19 CAR-γδT Cell Injection)in the treatment of recurrent/refractory antibody-mediated neurological autoimmune diseases.

Вмешательства

• Биопрепарат Universal CD19 CAR-γδT Cell Injection
  Biological: Allogeneic CD19 CAR-γδT cell following lymphodepletion with chemotherapy (cyclophosphamide and fludarabine) patients will be treated
• Препарат Cyclophosphamide
  Subjects will receive cyclophosphamide infusion on Days -5 to -3 prior to cell infusion.
• Препарат Fludarabine
  Subjects will receive fludarabine infusion on Days -5 to -3 prior to cell infusion.

Первичные конечные точки

• Incidence of Dose-Limiting Toxicities (DLTs) [Срок оценки: First infusion date of QH103 up to 28 days]
• Adverse Event [Срок оценки: 12 months]

Вторичные конечные точки (2)

• PK(Pharmacokinetics): Number and Copy Number of CD19 CAR-γδT cells [Срок оценки: 12 months]
• PD(Pharmacodynamics) ：Changes in cytokines and chemokines over time [Срок оценки: 12 months]

Критерии участия

Common Inclusion Criteria:

• Aged 18-75 years (inclusive), any gender.
• Female subjects of childbearing potential and male subjects with partners of childbearing potential must use medically approved contraception or practice abstinence during the study treatment period and for at least 6 months after the end of the study treatment. Female subjects of childbearing potential must have a negative serum HCG test within 7 days before study enrollment and must not be breastfeeding.
• The subject's expected survival, as judged by the investigator, is ≥12 weeks.
• Voluntarily participate in this trial and sign the informed consent form.

Disease-Specific Inclusion Criteria:

1、Multiple Sclerosis (MS): Clinically confirmed as progressive MS (including Primary Progressive PPMS or Secondary Progressive SPMS) or Relapsing-Remitting MS (RMS) according to the revised 2017 McDonald criteria. Disability status at screening must meet an EDSS score of 2-7 (inclusive) .For participants with RMS, despite standardized use of DMTs, they must have documented evidence meeting one of the following conditions prior to signing the informed consent:

• Two relapses were recorded within the first 2 years of screening;
• One recurrence was recorded within the first year prior to screening;
• Select the results of Gd-enhanced MRI scans that were positive within the previous year (if there is no record of a positive Gd-enhanced scan in the previous year, the results of the screening MRI scan can be used).

2、Neuromyelitis Optica Spectrum Disorder (NMOSD): Participants with AQP4 antibody-positive NMOSD meeting the 2015 IPND NMOSD diagnostic criteria, and meeting one of the following:

• Treatment with at least one immunosuppressant for over 1 year, or intolerance to immunosuppressant treatment, with suboptimal symptom control.
• At least 2 documented relapses within the last 12 months, or 3 documented relapses within the last 24 months with at least 1 relapse occurring within the 12 months prior to screening.

3、Autoimmune Encephalitis (AE): Participants with a clinical diagnosis of Autoimmune Encephalitis based on the 2016 International Diagnostic Criteria, meeting all of the following requirements:

• Positive for at least one relevant autoantibody;
• Inadequate symptom control with or intolerance to previous standardized treatment with glucocorticoids and at least one immunosuppressant/immunomodulator (including CD20 monoclonal antibody);
• An episode of autoimmune encephalitis within 3 months prior to signing the informed consent form;
• Disability status at screening meeting a modified Rankin Scale (mRS) score ≥ 2 or a CASE score ≥ 4 .

4、Chronic Inflammatory Demyelinating Polyneuropathy (CIDP): Participants diagnosed with antibody-positive CIDP according to the 2021 EAN/PNS diagnostic criteria, with an INCAT Disability Scale total score between 2 and 9, and meeting one of the following:

• Inadequate symptom control despite standardized use of at least one first-line therapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) for over 3 months;
• Intolerance to corticosteroids, intravenous immunoglobulin, and plasma exchange due to side effects or other reasons.

5、Myasthenia Gravis (MG): Participants diagnosed with antibody-positive MGFA Class II-IV Myasthenia Gravis according to the 2020 MGFA diagnostic criteria, with a Myasthenia Gravis Activities of Daily Living (MG-ADL) profile (Appendix 6) total score ≥ 6, and meeting one of the following:

• Standardized treatment with at least one immunosuppressant for over 1 year, with one of the following indicating inadequate control: (1) persistent weakness affecting daily life, (2) worsening MG symptoms and/or crisis episodes despite standard treatment, or (3) intolerance to immunosuppressant therapy;
• Requiring maintenance therapy with plasma exchange or intravenous immunoglobulin.

6、Anti-Myelin Oligodendrocyte Glycoprotein Immunoglobulin G Antibody----- - Associated Disease (MOGAD): Participants with a clinical diagnosis of MOGAD based on the 2023 International MOGAD Diagnostic Criteria, meeting all of the following:

• Positive for MOG autoantibody via cell-based assay (CBA);
• Disability status at screening meeting a modified Rankin Scale (mRS) score ≥ 2.
• Inadequate symptom control with or intolerance to previous standardized treatment with glucocorticoids and at least one immunosuppressant / immunomodulator (including CD20 monoclonal antibody).

7、Idiopathic Inflammatory Myopathies (IIM): Patients clinically diagnosed with refractory, antibody-positive Idiopathic Inflammatory Myopathy (IIM) based on the 2017 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria. At screening, at least one muscle enzyme (CK, AST, ALT, ALD, LDH) must be ≥1.5 times the upper limit of normal (ULN); OR the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) for dermatomyositis must be ≥6 (Appendix 7); OR there must be evidence of active myositis within the last 6 months from at least one of the following: MRI, electromyography, or muscle biopsy. The patient must test positive for at least one myositis-specific antibody (MSA), myositis-associated antibody (MAA), or antinuclear antibody (ANA). Additionally, they must meet one of the following criteria:

• Treatment with corticosteroids for at least 1 month, combined with standardized use of at least one immunosuppressant/immunomodulator (e.g., azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, leflunomide, intravenous immunoglobulin, etc.) for over 3 months, resulting in inadequate symptom control.
• Intolerance to the aforementioned conventional treatment regimens due to side effects or other reasons.

Критерии исключения

• History of severe drug allergy or allergic diathesis.
• Presence of or suspected uncontrolled or treatment-requiring fungal, bacterial, viral, or other infections.
• Organ function that does not meet the following requirements (except for abnormalities caused by the autoimmune disease itself):

• Bone Marrow Function: White blood cell count ≥1×10⁹/L; absolute neutrophil count ≥1×10⁹/L (no treatment with colony-stimulating factors within 2 weeks prior to the test); hemoglobin ≥60 g/L.
• Liver Function: ALT ≤3×ULN (except if elevated due to inflammatory myopathy); AST ≤3×ULN (except if elevated due to inflammatory myopathy); Indirect bilirubin (IBIL) ≤1.5×ULN (except for Gilbert's syndrome); Total bilirubin ≤3.0×ULN.
• Renal Function: Creatinine clearance (CrCl) ≥30 mL/min (eGFR ≥30 mL/min/1.73m²) (calculated by Cockcroft-Gault formula, except for acute decreases in CrCl due to the disease itself).
• Coagulation Function: International normalized ratio (INR) ≤1.5×ULN; Prothrombin time (PT) ≤1.5×ULN.
• Cardiac Function: Left ventricular ejection fraction (LVEF) ≥55% and no clinically significant cardiac disease.
• Subjects with a history indicative of congenital immunoglobulin deficiency.
• History of active/unresolved malignant tumors within the past 5 years.
• Subjects who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA titer above the detection limit; positive for hepatitis C virus (HCV) antibody with detectable peripheral blood HCV RNA; positive for human immunodeficiency virus (HIV) antibody; or positive for Treponema pallidumserology.
• History of definite psychiatric disorders or history of substance abuse involving psychotropic drugs that cannot be discontinued.
• Participation in any other clinical trial within 3 months prior to enrollment.
• Prior treatment with CAR-T cell therapy.
• History of severe adverse reactions to cyclophosphamide or fludarabine.
• History of other autoimmune diseases (e.g.,Crohn's disease, systemic lupus erythematosus) that, within the past 2 years, have resulted in end-organ damage or required systemic immunosuppressive therapy (excluding the disease populations specified for enrollment in the study protocol).
• Myasthenia gravis crisis not effectively controlled within 2 weeks prior to enrollment.
• History of cerebrovascular accident, including transient ischemic attack or stroke, within 6 months prior to enrollment.
• Male or female participants unwilling to practice contraception from the time of informed consent until 6 months after treatment completion.
• Any medical condition that may interfere with the assessment of the safety or efficacy of the study treatment.
• History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months prior to enrollment, requiring systemic anticoagulation therapy.
• Any other condition that, in the investigator's judgment, makes the subject unsuitable for participation in this study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology — Ухань

Идентификаторы

NCT: NCT07526493 · QH10310-NADs-01（0）

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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