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

Yudai Murayama, Hiroyuki Kawashima, Nobuhiro Kubo, Chansu Shin, Yasushi Kasahara, Masaru Imamura, Naoki Oike, Takashi Ariizumi, Akihiko Saitoh, Keichiro Mihara, Hajime Umezu, Akira Ogose, Chihaya Imai

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Abstract

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.

Original languageEnglish
Article number101227
JournalTranslational Oncology
Volume14
Issue number12
DOIs
Publication statusPublished - 12-2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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