A Safety and Efficacy Study of in Vivo CAR-T (HN2301) for Refractory Graves' Disease
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Incidence and severity of Adverse Events (AEs)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •(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.
排除标准
- •(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.
研究组 & 干预措施
In Vivo CAR-T Therapy for Refractory Graves' Disease
Participants with refractory Graves' disease will receive three to five intraveneous administrations of In Vivo CAR-T (HN2301).
干预措施: In Vivo CAR-T Therapy (Biological)
结局指标
主要结局
Incidence and severity of Adverse Events (AEs)
时间窗: From baseline to 3 months after infusion of HN2301
Assessment of the incidence and severity of treatment-emergent adverse events (AEs) occurring within 3 months after drug administration at the recommended dose.
Remission of Graves' disease
时间窗: From baseline to 12 months after infusion of HN2301
Proportion of remission will be calculated throughout 12 months after initial dose of HN2301. Remission is defined as euthyroid status without anti-thyroid medication.
次要结局
- Proportion of participants with ≥50% reduction of anti-thyrotropin receptor antibody (TRAb)(From baseline to 12 months after infusion of HN2301)
- Proportion of participants with ≥50% reduction of thyroid stimulating immunoglobulin (TSI)(From baseline to 12 months after infusion of HN2301)
- Change of TRAb levels compared to baseline(From baseline to 12 months after infusion of HN2301)
- Change of TSI levels compared to baseline(From baseline to 12 months after infusion of HN2301)
- Change of thyroid gland volume compared to baseline(From baseline to 12 months after infusion of HN2301)
- Change of thyroid peroxidase antibody (TPOAb) levels compared to baseline(From baseline to 12 months after infusion of HN2301)
- Change of Thyroglobulin antibody (TgAb) levels compared to baseline(From baseline to 12 months after infusion of HN2301)
- Proportion of CAR-T cells generated in peripheral blood after HN2301 administration(Day 0 to Day 14)
- Time to peak CAR-T Cell generation in peripheral blood after HN2301 administration(Day 0 to Day 14)
- Dynamic change of CAR gene copy number in peripheral blood after HN2301 administration(Day 0 to Day 14)
- Dynamic change of peripheral blood B lymphocyte cell count after HN2301 administration(From baseline to 12 months after infusion of HN2301)
- Dynamic change of serum interleukin-6 after HN2301 administration(From baseline to 12 months after infusion of HN2301)
- Dynamic change of serum tumor necrosis factor α (TNF-α) after HN2301 administration(From baseline to 12 months after infusion of HN2301)
- Dynamic change of serum immunoglobulin levels after HN2301 administration(From baseline to 12 months after infusion of HN2301)