In Vivo CAR-T for Refractory Graves' Disease

Официальное название

A Safety and Efficacy Study of in Vivo CAR-T (HN2301) for Refractory Graves' Disease

Обзор

Graves' disease is an autoimmune thyroid disorder characterized by the production of autoantibodies against the thyroid-stimulating hormone receptor (TRAb), leading to excessive thyroid hormone secretion and systemic manifestations. A subset of patients develop refractory disease, failing to achieve durable remission despite prolonged antithyroid therapy. This study aims to evaluate the safety and efficacy of HN2301, an in vivo CAR-T therapy in which host T lymphocytes are engineered and transformed to functional CAR-T cells via CD8 antibody-coated LNP delivery of CD19 CAR-mRNA. Participants with refractory Graves' disease will receive three to five administrations of HN2301 and will be regularly monitored for changes in thyroid function, TRAb levels, clinical response, and treatment-related adverse events. The study will provide preliminary evidence on whether HN2301 can induce sustained remission of refractory Graves' disease.

Вмешательства

• Биопрепарат In Vivo CAR-T Therapy
  Participants will receive 3 to 5 intravenous administrations of HN2301, given once every 2 days, according to the study dosing regimen.

Первичные конечные точки

• Incidence and severity of Adverse Events (AEs) [Срок оценки: From baseline to 3 months after infusion of HN2301]
• Remission of Graves' disease [Срок оценки: From baseline to 12 months after infusion of HN2301]

Вторичные конечные точки (12)

• Proportion of participants with ≥50% reduction of anti-thyrotropin receptor antibody (TRAb) [Срок оценки: From baseline to 12 months after infusion of HN2301]
• Proportion of participants with ≥50% reduction of thyroid stimulating immunoglobulin (TSI) [Срок оценки: From baseline to 12 months after infusion of HN2301]
• Change of TRAb levels compared to baseline [Срок оценки: From baseline to 12 months after infusion of HN2301]
• Change of TSI levels compared to baseline [Срок оценки: From baseline to 12 months after infusion of HN2301]
• Change of thyroid gland volume compared to baseline [Срок оценки: From baseline to 12 months after infusion of HN2301]
• Change of thyroid peroxidase antibody (TPOAb) levels compared to baseline [Срок оценки: From baseline to 12 months after infusion of HN2301]
• Change of Thyroglobulin antibody (TgAb) levels compared to baseline [Срок оценки: From baseline to 12 months after infusion of HN2301]
• Proportion of CAR-T cells generated in peripheral blood after HN2301 administration [Срок оценки: Day 0 to Day 14]
• Time to peak CAR-T Cell generation in peripheral blood after HN2301 administration [Срок оценки: Day 0 to Day 14]
• Dynamic change of CAR gene copy number in peripheral blood after HN2301 administration [Срок оценки: Day 0 to Day 14]
• Dynamic change of peripheral blood B lymphocyte cell count after HN2301 administration [Срок оценки: From baseline to 12 months after infusion of HN2301]
• Dynamic change of serum interleukin-6 after HN2301 administration [Срок оценки: From baseline to 12 months after infusion of HN2301]

Критерии участия

Inclusion Criteria (Participants must meet all of the following criteria to be eligible for this study):

• Age 18-75 years (inclusive), male or female.
• Refractory Graves' disease, defined as meeting at least one of the following: a) Continuous antithyroid drug (ATD) therapy for ≥3 years without achieving criteria for ATD discontinuation; b) Meeting criteria for ATD discontinuation but experiencing ≥2 relapses after ATD withdrawal.
• Positive serum TRAb.
• Willing to use effective contraception for 12 months after study drug administration.
• Voluntarily agrees to participate in the study, has signed the informed consent form, and is able to comply with study procedures and follow-up requirements.

Exclusion Criteria (Participants meeting any of the following criteria will be excluded from the study):

• History of severe drug allergy or known allergic predisposition.
• Presence or suspected presence of uncontrolled active infection.
• History of major organ transplantation (e.g., heart, lung, liver, kidney) or bone marrow/hematopoietic stem cell transplantation.
• Presence of significant heart disease, such as angina, myocardial infarction, heart failure, or clinically significant arrhythmias.
• Receipt of any mRNA-LNP product or other lipid nanoparticle (LNP)-based therapy within the past 2 years.
• Receipt of a live vaccine within 30 days prior to screening.
• History of malignant tumors.
• Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA above the detection limit; positive hepatitis C virus (HCV) antibody with detectable HCV RNA; positive human immunodeficiency virus (HIV) antibody; or positive syphilis test.
• Presence of psychiatric disorders or severe cognitive impairment.
• Hematologic dysfuction at screening, defined as any of the following: a. Neutrophil count < 1.8 × 10⁹/L, b. Hemoglobin < 110 g/L, c. Platelet count < 50 × 10⁹/L
• Impaired liver function, defined as any of the following: Alanine aminotransferase (ALT) > 3 × ULN, Aspartate aminotransferase (AST) > 3 × ULN, Total bilirubin > 2.5 × ULN.
• Impaired renal function: creatinine clearance rate (CrCl) < 60 mL/min (Cockcroft-Gault formula).
• Left ventricular ejection fraction (LVEF) < 55%.
• Coagulation abnormalities, defined as either: International normalized ratio (INR) > 1.5 × ULN, Prothrombin time (PT) > 1.5 × ULN
• Pregnant or breastfeeding women.
• Any other condition that, in the opinion of the investigator, would make the participant unsuitable for the 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

• Zhongshan Hospital Fudan University — Шанхай

Идентификаторы

NCT: NCT07333677 · B2025-805

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗