TSH Ligand-Based CAR-T Cell Effectively Eradicates TSHR-Positive Thyroid Cancer with Favorable Safety Profile

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• CAR-T therapy faces challenges in solid tumors due to antigen scarcity and CAR molecule immunogenicity.
• Thyroid-stimulating hormone receptor (TSHR) is specifically expressed in differentiated thyroid cancer (DTC), presenting an ideal target.
• TSHR expression is absent in normal tissues, minimizing off-target effects.

Purpose of the Study:

• To develop a novel CAR-T therapy targeting TSHR for differentiated thyroid cancer (DTC).
• To overcome CAR immunogenicity by engineering a CAR molecule using TSH (TSH-CAR) as the antigen-binding domain.
• To evaluate the preclinical efficacy and safety of TSH-CAR-T cells.

Main Methods:

• Engineered a novel CAR molecule (TSH-CAR) using TSH as the antigen-binding domain.
• Assessed TSH-CAR-T cell antitumor activity against TSHR-positive DTC cell lines in vitro.
• Evaluated tumor eradication and remission in thyroid cancer xenograft models.
• Assessed safety using a murine TSH-CAR (mTSH-CAR-T) in syngeneic mouse models.

Main Results:

• TSH-CAR-T cells exhibited effective in vitro antitumor activity, cytokine release (IFNγ, IL-2), and proliferation.
• Complete tumor eradication and sustained remission were achieved in preclinical thyroid cancer models.
• mTSH-CAR-T cells controlled tumor growth without significant off-target effects, except for transient thyroid follicle impairment.

Conclusions:

• TSH-CAR-T cells demonstrate potent preclinical efficacy against TSHR-positive differentiated thyroid cancer.
• The engineered TSH-CAR-T therapy shows a favorable safety profile, with acceptable transient side effects.
• These findings strongly support the clinical translation of TSH-CAR-T for metastatic and radioiodine-resistant DTC.