Graves Disease
Conditions
Keywords
CAR-T, refractory Graves disease, TSH receptor antibody
Brief summary
Graves' disease is an autoimmune disease. The TSH receptor antibody(TRab) produced by B cells drives the production of thyroid hormone, which causes systemic disorders and thyroid eye disease. The purpose of this study is to investigate the efficacy and safety of allogeneic anti-CD19 CAR-T for refractory Graves' disease. The participants with refractory Graves' disease will receive a single dose of allogeneic anti-CD19 CAR-T and be regularly seen for the change of serum TRab, FT3, FT4 and clinical presentations, as well as any adverse events.
Interventions
BIOLOGICALAllogeneic CAR-T
The participants will receive one dose of allogeneic CAR-T
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 65 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with refractory Graves disease, which is defined as meeting any one of the following criteria: a. Failure to discontinue medication after continuous standard antithyroid therapy for ≥ 3 years; b. Hyperthyroid state requiring medication after receiving ≥ 2 times of radioiodine therapy (with the last dose of radioiodine administered at least 6 months prior); c. Relapse ≥ 2 times after cessation of medication upon meeting the criteria for treatment discontinuation. * Serum TRAb ≥ 3 times greater than normal range (≥ 5 IU/L) * Positive expression of CD19 on peripheral blood B cells determined by flow cytometry. * Participation in this clinical study is willing to sign an informed consent with good compliance with treatment and follow-up. (Criteria for treatment discontinuation is define as receiving continuous anti-thyroid drug therapy for ≥18 months, and maintaining euthyroid status for ≥6 months, plus negative TRAb and TSI. Relapse is defined as recurrence of hyperthyroidism and positive TRAb/TSI after meeting the criteria for treatment discontinuation and stopping medication.)
Exclusion criteria
* History of severe drug allergies or allergic constitution; * Presence or suspicion of uncontrolled infections requiring intravenous treatment (fungal, bacterial, viral or other); * Presence of central nervous system disorders (including epilepsy, psychosis, cerebrovascular accident, encephalitis, CNS vasculitis, etc); * Presence of clinically significant heart diseases (e.g., angina pectoris, myocardial infarction, heart failure, severe arrhythmias, etc); * Subjects with congenital immunoglobulin deficiency; * Patients with malignant tumors; * Subjects who are: 1. HBsAg or HBcAb positive with detectable peripheral blood HBV DNA; 2. HCV antibody positive with detectable HCV RNA; 3. Positive HIV antibody; 4. Syphilis test positive; * Subjects with psychiatric disorders or severe cognitive dysfunction; * Hematopoietic function: a. White blood cell count \< 3.5×10\^9/L b. Neutrophil count \< 1.5 x 10\^9/L; c. Hemoglobin \< 110g/L. * Liver function: ALT\> 3×ULN, AST \> 3×ULN, TBIL \> 2.5×ULN. * Renal function: creatinine clearance rate (CrCl) \< 60 ml/minute (calculated based on Cockcroft/Fault formula). * Cardiac function: LVEF \< 55% * Coagulation function: International standardized ratio (INR) ≥ 1.5×ULN, prothrombin time(PT) \>1.5 × ULN. * Participation in other clinical trials within 3 months prior to enrollment; * Pregnancy or planning pregnancy; * Other conditions considered by investigators as unsuitable for participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Remission of Graves disease | From baseline to 12 months after infusion of CAR-T cells | Sustained euthyroid status without anti-thyroid medication for ≥3 months |
| Incidence of Adverse Events | From baseline to 6 months after infusion of CAR-T cells | Assessed using the CTCAE v5.0 standards |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| thyroid peroxidase antibody (TPOAb) | From baseline to 12 months after infusion of CAR-T cells | Serum TPOAb titers at 6 months and 12 months after infusion of CAR-T cells |
| Thyroglobulin antibody (TgAb) | From baseline to 12 months after infusion of CAR-T cells | Serum TgAb titers at 6 months and 12 months after infusion of CAR-T cells |
| Anti-Thyrotropin receptor antibody (TRAb) | From baseline to 12 months after infusion of CAR-T cells | Serum TRAb titers at 6 months and 12 months after infusion of CAR-T cells |
| PK parameters - CAR gene copy number | From baseline to 3 months after infusion of CAR-T cells | Dynamic change in the CAR gene copy number in peripheral blood after infusion of CAR-T cells |
| PK parameters - CAR-T cell count | From baseline to 3 months after infusion of CAR-T cells | Dynamic change of CAR-T cell count in peripheral blood after infusion of CAR-T cells |
| Thyroid volume | From baseline to 12 months after infusion of CAR-T cells | Size of thyroid measured and calculated by ultrasound at 6 months and 12 months after infusion of CAR-T cells |
| Thyroid stimulating immunoglobulin (TSI) | From baseline to 12 months after infusion of CAR-T cells | Serum TSI titers at 6 months and 12 months after infusion of CAR-T cells |
Countries
China
Contacts
Primary ContactJingjing JIANG, MD, PhD
Outcome results
None listed