Effectiveness of 4-1BB-costimulated HER2-targeted chimeric antigen receptor T cell therapy for synovial sarcoma

Translational Oncology

卷:14

Chihaya Imai¹  Hiroyuki Kawashima²  Yudai Murayama³  Keichiro Mihara³  Chansu Shin³  Yasushi Kasahara³  Naoki Oike³  Masaru Imamura³  Takashi Ariizumi⁴  Akihiko Saitoh⁴  Nobuhiro Kubo⁴  Akira Ogose⁵  Hajime Umezu⁶ 

[1] Dental Hospital, Niigata, Japan;

[2] Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;

[3] Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuou-ku, Niigata City, Niigata 951-8510, Japan;

[4] Division of Pathology, Niigata University Medical &

[5] International Regenerative Medical Center, Fujita Health University, Aichi, Japan;

关键词: Synovial sarcoma;    HER2;    Chimeric antigen receptor;    T cell;    Cancer immunotherapy;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown