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GD2-specific chimeric antigen receptor-modified T cells targeting retinoblastoma - assessing tumor and T cell interaction.

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机构: [a]Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkok 10700, Thailand [b]Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand [c]University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, Florida, United States [d]Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States [e]Shenzhen Geno-Immune Medical Institute, 2nd FL. 6 Yuexing 2nd Rd., Nanshan Dist., Shenzhen, China [f]Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand [g]Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand [h]Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand [i]School of Medicine, University of Electronic Science and Technology of China, Sichuan, China
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A novel disialoganglioside 2 (GD2)-specific chimeric antigen receptor (CAR)-modified T cell therapy against retinoblastoma (RB) were generated. GD2-CAR consists of a single-chain variable fragment (scFv) derived from a monoclonal antibody, hu3F8, that is linked with the cytoplasmic signaling domains of CD28, 41BB, a CD3ζ, and an inducible caspase 9 death fusion partner. GD2 antigen is highly expressed in Y79RB cell line and in several surgical RB tumor specimens. In vitro co-culture experiments revealed the effective killing of Y79RB cells by GD2-CAR T cells, but not by control CD19-CAR T cells. The killing activities of GD2-CAR T cells were diminished when repeatedly exposed to the tumor, due to an attenuated expression of GD2 antigen on tumor cells and upregulation of inhibitory molecules of the PD1 and PD-L1 axis in the CAR T cells and RB tumor cells respectively. This is the first report to describe the potential of GD2-CAR T cells as a promising therapeutic strategy for RB with the indication of potential benefit of combination therapy with immune checkpoint inhibitors. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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出版当年[2021]版:
大类 | 3 区 医学
小类 | 3 区 肿瘤学
最新[2023]版:
大类 | 2 区 医学
小类 | 3 区 肿瘤学
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