Graves' Disease
Conditions
Keywords
refractory Graves' disease, TSH receptor antibody, in vivo CAR-T
Brief summary
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.
Interventions
BIOLOGICALIn 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.
Sponsors
Shanghai Zhongshan Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of Adverse Events (AEs) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with ≥50% reduction of anti-thyrotropin receptor antibody (TRAb) | From baseline to 12 months after infusion of HN2301 | Percentage of participants achieving a ≥50% reduction of TRAb throughout 12 months after initial dose of HN2301, as compared with baseline. |
| Proportion of participants with ≥50% reduction of thyroid stimulating immunoglobulin (TSI) | From baseline to 12 months after infusion of HN2301 | Percentage of participants achieving a ≥50% reduction of TSI througout 12 months after initial dose of HN2301, as compared with baseline. |
| Change of TRAb levels compared to baseline | From baseline to 12 months after infusion of HN2301 | TRAb levels will be measured from baseline to 12 months after initial dose of HN2301 |
| Change of TSI levels compared to baseline | From baseline to 12 months after infusion of HN2301 | TSI levels will be measured from baseline to 12 months after initial dose of HN2301 |
| Change of thyroid gland volume compared to baseline | From baseline to 12 months after infusion of HN2301 | Size of thyroid will be measured and calculated by ultrasound from baseline to 12 months after initial dose of HN2301 |
| Change of thyroid peroxidase antibody (TPOAb) levels compared to baseline | From baseline to 12 months after infusion of HN2301 | TPOAb levels will be measured from baseline to 12 months after initial dose of HN2301 |
| Change of Thyroglobulin antibody (TgAb) levels compared to baseline | From baseline to 12 months after infusion of HN2301 | TgAb levels will be measured from baseline to 12 months after initial dose of HN2301 |
| Proportion of CAR-T cells generated in peripheral blood after HN2301 administration | Day 0 to Day 14 | Proportion of CAR-T cells generated in peripheral blood after infusion of HN2301 |
| Time to peak CAR-T Cell generation in peripheral blood after HN2301 administration | Day 0 to Day 14 | Time to reach the peak level of CAR-T cells generated in peripheral blood after infusion of HN2301 |
| 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 | — |
Countries
China
Contacts
CONTACTJingjing JIANG, MD, PhD
Outcome results
None listed