TY - JOUR
T1 - Effectiveness of 4-1BB-costimulated HER2-targeted chimeric antigen receptor T cell therapy for synovial sarcoma
AU - Murayama, Yudai
AU - Kawashima, Hiroyuki
AU - Kubo, Nobuhiro
AU - Shin, Chansu
AU - Kasahara, Yasushi
AU - Imamura, Masaru
AU - Oike, Naoki
AU - Ariizumi, Takashi
AU - Saitoh, Akihiko
AU - Mihara, Keichiro
AU - Umezu, Hajime
AU - Ogose, Akira
AU - Imai, Chihaya
N1 - Funding Information:
This work was supported by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research, JSPS KAKENHI Grant Number 19K08317 (to CI), 21K07213 (to MI), and 21K09197 (to AO).
Funding Information:
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the ethical committee of Niigata University School of Medicine (approval #2015-2686). Informed consent was obtained from all volunteers who participated in this study. Not applicable, The data presented in this study are available upon request from the corresponding author. Yudai Murayama: Methodology, Investigation, Validation, Formal analysis, Writing - Original Draft; Hiroyuki Kawashima: Conceptualization, Resources, Supervision; Nobuhiro Kubo: Investigation; Chansu Shina: Methodology, Resources; Yasushi Kasahara: Methodology, Resources; Masaru Imamura: Funding acquisition; Naoki Oike: Resources; Takashi Ariizumi: Resources; Akihiko Saitoh: Resources; Keichiro Mihara: Resources; Hajime Umezu: Investigation; Akira Ogose: Conceptualization, Funding acquisition; Chihaya Imai: Project administration, Conceptualization, Resources, Supervision, Funding acquisition, Writing - Review & Editing. This work was supported by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research, JSPS KAKENHI Grant Number 19K08317 (to CI), 21K07213 (to MI), and 21K09197 (to AO). We gratefully acknowledge Ms. Yuko Suzuki, Ms. Ai Itoh, and Ms. Yuko Saito (Department of Pediatrics, Niigata University) as well as Ms. Keiko Tanaka and Mr. Yoshiaki Tanaka (Division of Orthopedic Surgery, Niigata University) for their excellent technical assistance, and Ms. Masami Yamagishi and Ms. Nobuko Tsuchida (Department of Pediatrics) for secretarial support. We would like to thank Editage (www.editage.com) for English language editing.
Publisher Copyright:
© 2021
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.tranon.2021.101227
DO - 10.1016/j.tranon.2021.101227
M3 - Article
AN - SCOPUS:85115228049
SN - 1944-7124
VL - 14
JO - Translational Oncology
JF - Translational Oncology
IS - 12
M1 - 101227
ER -