Translational Oncology ( IF 4.5 ) Pub Date : 2021-09-21 , DOI: 10.1016/j.tranon.2021.101227 Yudai Murayama 1 , Hiroyuki Kawashima 2 , Nobuhiro Kubo 3 , Chansu Shin 3 , Yasushi Kasahara 3 , Masaru Imamura 3 , Naoki Oike 2 , Takashi Ariizumi 2 , Akihiko Saitoh 3 , Keichiro Mihara 4 , Hajime Umezu 5 , Akira Ogose 6 , Chihaya Imai 3
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Background
Synovial sarcoma is a rare malignant soft-tissue tumor that is prevalent in adolescents and young adults, and poor prognosis has been reported in patients with metastatic lesions. Chimeric antigen receptor (CAR) T-cell therapy is an emerging novel therapy for solid tumors; however, its application in synovial sarcoma has not yet been explored.
Methods
A novel human epidermal growth factor receptor 2 (HER2)-targeted CAR containing scFv-FRP5, CD8α hinge and transmembrane domains as well as 4-1BB costimulatory and CD3ζ signaling domains was developed. Three synovial sarcoma cell lines that expressed the fusion transcript SS18-SSX1/2/4 were used in the study. Cytokine secretion assay, cytotoxicity assay, and real-time cell analysis experiments were conducted to confirm the function of T cells transduced with the CAR gene.
Results
High cell-surface expression of HER2 was observed in all the cell lines. HER2-targeted/4-1BB-costimulated CAR T cells specifically recognized the synovial sarcoma cells, secreted interferon gamma and tumor necrosis factor alpha, and exerted cytotoxic effects in these cells.
Conclusion
To the best of our knowledge, this is the first study to indicate that HER2-targeted CAR T cells are directly effective against molecularly defined synovial sarcoma cells. Furthermore, our findings might set the basis for developing improved CAR T cell-based therapies for chemo-refractory or relapsed synovial sarcoma.
中文翻译：
4-1BB 共刺激 HER2 靶向嵌合抗原受体 T 细胞治疗滑膜肉瘤的有效性
背景
滑膜肉瘤是一种罕见的恶性软组织肿瘤，多见于青少年和年轻成人，有转移性病变的患者预后较差。嵌合抗原受体 (CAR) T 细胞疗法是一种新兴的实体瘤新疗法；然而，尚未探索其在滑膜肉瘤中的应用。
方法
开发了一种新型人表皮生长因子受体 2 (HER2) 靶向 CAR，其中包含 scFv-FRP5、CD8α 铰链和跨膜结构域以及 4-1BB 共刺激和 CD3ζ 信号结构域。研究中使用了三种表达融合转录物 SS18-SSX1/2/4 的滑膜肉瘤细胞系。进行细胞因子分泌测定、细胞毒性测定和实时细胞分析实验以确认转导 CAR 基因的 T 细胞的功能。
结果
在所有细胞系中均观察到 HER2 的高细胞表面表达。HER2 靶向/4-1BB 共刺激 CAR T 细胞特异性识别滑膜肉瘤细胞，分泌干扰素 γ 和肿瘤坏死因子 α，并在这些细胞中发挥细胞毒性作用。
结论
据我们所知，这是第一项表明 HER2 靶向 CAR T 细胞对分子定义的滑膜肉瘤细胞直接有效的研究。此外，我们的研究结果可能为开发基于 CAR T 细胞的改良疗法治疗化疗难治性或复发性滑膜肉瘤奠定基础。
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