CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer
CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer
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靶向 TSHR 的 CAR-T 细胞显示出针对分化型甲状腺癌的安全性和有效的临床前活性
DOI：
10.1210/clinem/dgab819
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发表时间：
2021-12-03
影响因子：
5.8
通讯作者：
Li, Xingrui
中科院分区：
文献类型：
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作者：
Li, Hanning;Zhou, Xiang;Li, Xingrui
嵌合抗原受体T细胞（CAR-Ts）已在血液癌症中表现出显著的疗效，但尚未转化为治疗实体瘤。限制CAR-T治疗的重大障碍来自于实体瘤上缺乏可以安全靶向的差异表达的细胞表面分子。在这里，我们提出TSH受体（TSHR）作为分化型甲状腺癌（DTC）CAR-T治疗的假定靶点。方法采用生物信息学分析和免疫组化技术对甲状腺癌组织及多种脏器进行大规模筛查，检测TSHR的表达情况。使用3种先前描述的单克隆抗体，我们产生了3种第三代CAR-T。我们通过T细胞功能和杀伤试验测试了抗TSHR CAR-T的体外活性。然后，我们在DTC的异种移植小鼠模型中测试了临床前治疗效果，并分析了小鼠的身体状况和组织学异常，以评估抗TSHR CAR-T的安全性。结果TSHR在90.8%（138/152）的甲状腺乳头状癌、89.2%（33/37）的甲状腺滤泡状癌、78.2%（18/23）的颈淋巴结转移癌和86.7%的甲状腺放射性碘抵抗性疾病中呈高度均匀表达。我们从单克隆抗体M22、K1-18和K1-70开发了3种新型抗TSHR CAR-T;所有3种CAR-T均在体外介导显著的抗肿瘤活性。其中，我们证明了K1-70 CAR-T在体内具有治疗功效，并且没有观察到明显的毒性。结论TSHR是CAR-T治疗DTC的潜在靶抗原。抗TSHR CAR-T可能是局部复发或远处转移甲状腺癌患者的治疗选择，应在精心设计的临床试验中进行测试。
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.