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

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Abstract

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.

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Xiao, W., Wang, J., Wen, X., Xu, B., Que, Y., Yu, K., … Zhang, X. (2020). Chimeric antigen receptor-modified T-cell therapy for platelet-derived growth factor receptor α-positive rhabdomyosarcoma. Cancer, 126(S9), 2093–2100. https://doi.org/10.1002/cncr.32764

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