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Chimeric antigen receptor-modified T-cell therapy for platelet-derived growth factor receptor α-positive rhabdomyosarcoma.

Authors
  • Xiao, Wei1, 2
  • Wang, Jinghua3
  • Wen, Xizhi1, 2
  • Xu, Bushu1, 2
  • Que, Yi1, 2
  • Yu, Kuai2, 4
  • Xu, Liping2, 4
  • Zhao, Jingjing1, 2
  • Pan, Qiuzhong1, 2
  • Zhou, Penghui2, 4
  • Zhang, Xing1, 2
  • 1 Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, Guangzhou, China. , (China)
  • 2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. , (China)
  • 3 Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. , (China)
  • 4 Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China. , (China)
Type
Published Article
Journal
Cancer
Publisher
Wiley (John Wiley & Sons)
Publication Date
May 01, 2020
Volume
126 Suppl 9
Pages
2093–2100
Identifiers
DOI: 10.1002/cncr.32764
PMID: 32293729
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

New immunotherapeutic approaches are urgently needed for metastatic rhabdomyosarcoma, which is associated with poor survival and unsatisfactory treatment outcomes. Platelet-derived growth factor receptor α (PDGFRA) plays an essential role in the onset and development of rhabdomyosarcoma and is a new potential therapeutic target for rhabdomyosarcoma. The objective of this study was to generate humanized PDGFRA single-chain variable fragment-based chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) against PDGFRA-positive rhabdomyosarcoma. PDGFRA antigen expression was evaluated in specimens from patients with rhabdomyosarcoma. CAR-T cells containing a PDGFRA-specific single-chain variable fragment was developed in combination with a 4-1BB costimulatory domain and a CD3-ζ signaling domain. Specific cytotoxic effects of PDGFRA CAR-T cells, T-cell proliferation, and cytokine secretion were investigated in vitro and in vivo. PDGFRA CAR-T cells produced large amounts of immune-promoting cytokines, including interleukin 2, tumor necrosis factor α, and interferon γ, and exhibited efficient cytotoxic activity toward human PDGFRA-overexpressing rhabdomyosarcoma cells in vitro. In a subcutaneous xenograft model, CAR-T cells were more effective against PDGFRA-overexpressing rhabdomyosarcoma than against rhabdomyosarcoma with low PDGFRA expression in terms of tumor regression and patient survival. Expanded CAR-T cells also were detected in peripheral blood. The current study demonstrates for the first time that the PDGFRA antigen is a promising target for CAR-T-cell therapy in rhabdomyosarcoma and likely in a wide spectrum of other PDGFRA-expressing cancers. © 2020 American Cancer Society.

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