PET Imaging of Thyroid-Stimulating Hormone Receptor (TSHR) in Oncocytic Thyroid Carcinoma for Monitoring TSHR CAR T-Cell Therapy Response.

Abstract

Oncocytic thyroid carcinoma (OTC) is often aggressive and refractory to radioiodine therapy, which is the current standard of care for metastatic thyroid cancer. The thyroid-stimulating hormone receptor (TSHR) regulates thyroid function and metabolism and is highly expressed in the thyroid gland and most thyroid tumors including OTC. Here, we report positron emission tomography (PET) imaging of radiolabeled TSHR antibody for detecting tumoral TSHR expression and monitoring TSHR chimeric antigen receptor (CAR) T-cell therapy response in an OTC mouse model. Radiotracer ⁸⁹Zr-DFO-TSHR-Ab was prepared as previously reported for PET imaging of TSHR expression. Tissue microarray analysis confirmed TSHR expression in both normal thyroid and OTC tumors. A human OTC xenograft model was established by subcutaneous injection of XTC.UC1 cells into NSG mice. PET imaging and biodistribution studies of TSHR expression were subsequently conducted in this model to assess TSHR-expression change before and after TSHR CAR T-cell therapy. TSHR-targeted CAR T-cells were administered intravenously, and longitudinal PET/CT imaging with ⁸⁹Zr-DFO-TSHR-Ab was performed at 24, 72, and 120 h postinjection to monitor tumor response. Eight weeks later, the same mice were rechallenged with XTC.UC1 cells in the contralateral flank to assess long-term therapeutic efficacy and immune memory through serial PET/CT imaging. PET imaging and biodistribution studies demonstrated that this radiotracer effectively detected TSHR-expressing OTC, with reasonable tumor uptake and imaging contrast. Following CAR T-cell therapy, TSHR PET showed significantly decreased tumor uptake, consistent with TSHR-targeted cell immunotherapy response with attenuated TSHR expression. These findings suggest ⁸⁹Zr-DFO-TSHR-Ab enables noninvasive identification of OTC tumors and real-time monitoring of response to TSHR-targeted CAR T-cell therapy.