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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
Statement of
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
Neoplasm Metastasis
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
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