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https://hdl.handle.net/2440/101586
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Type: | Journal article |
Title: | GD2-specific CAR T cells undergo potent activation and deletion following antigen encounter but can be protected from activation-induced cell death by PD-1 blockade |
Author: | Gargett, T. Yu, W. Dotti, G. Yvon, E. Christo, S. Hayball, J. Lewis, I. Brenner, M. Brown, M. |
Citation: | Molecular Therapy, 2016; 24(6):1135-1149 |
Publisher: | Nature Publishing Group |
Issue Date: | 2016 |
ISSN: | 1525-0016 1525-0024 |
Statement of Responsibility: | Tessa Gargett, Wenbo Yu, Gianpietro Dotti, Eric S Yvon, Susan N Christo, John D Hayball, Ian D Lewis, Malcolm K Brenner and Michael P Brown |
Abstract: | Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological "space", functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1(+) tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients. |
Keywords: | T-Lymphocytes Cell Line, Tumor Animals Humans Mice Melanoma Neoplasm Metastasis Gangliosides Receptors, Antigen, T-Cell Xenograft Model Antitumor Assays Lymphocyte Activation Cell Survival Antibodies, Monoclonal, Humanized Programmed Cell Death 1 Receptor |
Rights: | © The American Society of Gene & Cell Therapy |
DOI: | 10.1038/mt.2016.63 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1010386 |
Published version: | http://dx.doi.org/10.1038/mt.2016.63 |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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