CoupledCAR technology for treating thyroid cancer.
Authors: Xiao Lei , Liu Xingchen , Zhou Keshu , Liu Yu , Huang Yong , Pu Chengfei , Cao Zhiyuan , Zhu Ruihong , Tang Haiyang , Huang Zhipeng , Yang Hang , Huang Xi , Song Yongping , Liu Renbin , Wu Zhao , Lu Victor 
Published: June 2021

e14507 Background: Chimeric antigen receptor modified T-cells (CAR-T) have demonstrated remarkable clinical efficacy in the treatment of B-cell malignancies. Significant challenges restrict their application across solid tumors due to multiple obstacles, including the lack of robust in vivo CAR-T cell expansion and persistence in the immunosuppressive tumor microenvironment. Methods: To address these difficulties, we generated CAR-T cells using a novel CoupledCAR technology. Specifically, we engineered CoupledCAR-T cells with lentiviral vectors encoding an anti-thyroid stimulating hormone receptor (TSHR) CAR molecule. In vitro co-culture experiments showed that TSHR CAR-T cells specifically recognized and subsequently killed TSHR-positive tumor cells. Animal model experiments showed that TSHR CAR-T cells inhibited the proliferation of TSHR-positive tumor cells. Results: Patient 1: Male, 64Y, Papillary Thyroid Carcinoma. In May 2017, his Thyroid cancer was diagnosed, bilateral total thyroidectomy, and right cervical lymph node functional dissection were performed in Jun 2018, followed by iodine 131 isotope therapy. In December 2018, bilateral multiple cervical lymph nodes were enlarged, especially on the right side. In February 2019, right neck lymphadenectomy was performed. One month after infusion (M1) of the anti-TSHR CoupledCAR-T cells, the patient was evaluated as PR. Three months after infusion (M3), the patient was evaluated as CR, and the patient's CR lasted from M3 to M12 after infusion of the CoupledCAR-T cells. We are still following the patient for long-term clinical effects. Patient 2: Female, 60Y, Thyroid Carcinoma: In Aug 2013, a "double lobectomy of the thyroid gland” was performed. From Oct 2013 to Jan 2014, she received iodine 131 isotope therapy. In Sep 2014, she was diagnosed with iodine-resistant thyroid cancer. From Sep to Jan 2016, 5 cycles of chemotherapy were performed. In Jun 2016, she enrolled in the Anlotinib experimental group. In Mar 2019, multiple metastases in both lungs and multiple enlarged lymph nodes in the mediastinum were observed. At month 1 (M1) post cell infusion, the patient was evaluated as PR (Partial Response): the tumor volume in the right lower lobe of the lung was reduced by approximately 67.51% (decreased from 65*55mm to 42*39mm). Three months after infusion (M3), the tumor volume was reduced by approximately 73.54% and SUV max value decreased from 14.9 to 2.8. Therefore, the patient was evaluated as nCR (near complete remission). Conclusions: In summary, we showed that TSHR is an attractive and specific target for treating thyroid cancer and our anti-TSHR CoupledCAR-T cells are safe and effective for treating thyroid cancer. Recruitment is ongoing to evaluate the safety and efficacy of our CoupledCAR-T cells. Further, since our CoupledCAR technology is a platform technology, we are developing additional CoulpledCAR-T cells to treat other solid tumors using different target tumor markers.