CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer

  • J Clin Endocrinol Metab. 2022 Mar 24;107(4):1110-1126. doi: 10.1210/clinem/dgab819.
Hanning Li  1  2  3 ,  Xiang Zhou  4 ,  Ge Wang  1  2  3 ,  Dongyu Hua  5 ,  Shuyu Li  1  2  3 ,  Tao Xu  1  2  3  6 ,  Menglu Dong  1  2  3 ,  Xiaoqing Cui  1  2  3 ,  Xue Yang  1  2  3 ,  Yonglin Wu  1  2  3 ,  Miaomiao Cai  4 ,  Xinghua Liao  4 ,  Tongcun Zhang  4 ,  Zhifang Yang  1  2  3 ,  Yaying Du  1  2  3 ,  Xingrui Li  1  2  3
Affiliations
  • 1. Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430030, People's Republic of China.
  • 2. Laboratory of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430030, People's Republic of China.
  • 3. Laboratory of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430030, People's Republic of China.
  • 4. College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People's Republic of China.
  • 5. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430030, People's Republic of China.
  • 6. Department of Obstetrics and Gynecology, Cancer Biology research center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430030, People's Republic of China.
PMID: 34751400 DOI: 10.1210/clinem/dgab819
Abstract

Background: Chimeric antigen receptor T cells (CAR-Ts) have demonstrated remarkable efficacy in hematological cancers but have not yet translated in treating solid Tumors. The significant hurdles limiting CAR-T therapy were from a paucity of differentially expressed cell surface molecules on solid Tumors that can be safely targeted. Here, we present TSH Receptor (TSHR) as a putative target for CAR-T therapy of differentiated Thyroid Cancer (DTC).

Methods: We undertook a large-scale screen on Thyroid Cancer tissues and multiple internal organs through bioinformatical analysis and immunohistochemistry to date TSHR expression. Using 3 previously described Monoclonal Antibodies, we generated 3 third-generation CAR-Ts. We tested anti-TSHR CAR-T in vitro activity by T-cell function and killing assay. Then we tested preclinical therapeutical efficacy in a xenograft mouse model of DTC and analyzed mice's physical conditions and histological abnormalities to evaluate anti-TSHR CAR-T's safety.

Results: TSHR is highly and homogeneously expressed on 90.8% (138/152) of papillary Thyroid Cancer, 89.2% (33/37) of follicular Thyroid Cancer, 78.2% (18/23) of cervical lymph node metastases, and 86.7% of radioactive iodine resistance diseases. We developed 3 novel anti-TSHR CAR-Ts from Monoclonal Antibodies M22, K1-18, and K1-70; all 3 CAR-Ts mediate significant antitumor activity in vitro. Among these, we demonstrate that K1-70 CAR-T can have therapeutical efficacy in vivo, and no apparent toxicity has been observed.

Conclusion: TSHR is a latent target antigen of CAR-T therapy for DTC. Anti-TSHR CAR-T could represent a therapeutic option for patients with locoregional relapsed or distant metastases of Thyroid Cancer and should be tested in carefully designed clinical trials.

Keywords
CAR-T; TSH receptor; adoptive transfer therapy; differentiated thyroid cancer; radioactive iodine refractory DTC; targeted therapy; tumor-specific antigens.
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