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Chimeric antigen receptor‐modified T‐cell therapy for platelet‐derived growth factor receptor α‐positive rhabdomyosarcoma
Author(s) -
Xiao Wei,
Wang Jinghua,
Wen Xizhi,
Xu Bushu,
Que Yi,
Yu Kuai,
Xu Liping,
Zhao Jingjing,
Pan Qiuzhong,
Zhou Penghui,
Zhang Xing
Publication year - 2020
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.32764
Subject(s) - pdgfra , chimeric antigen receptor , rhabdomyosarcoma , cancer research , medicine , cytotoxic t cell , cytokine , growth factor receptor , t cell , immunology , immune system , biology , receptor , in vitro , pathology , sarcoma , biochemistry , gist , stromal cell
Background 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. Methods 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. Results 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. Conclusions 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.