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https://hdl.handle.net/2440/101586
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dc.contributor.author | Gargett, T. | - |
dc.contributor.author | Yu, W. | - |
dc.contributor.author | Dotti, G. | - |
dc.contributor.author | Yvon, E. | - |
dc.contributor.author | Christo, S. | - |
dc.contributor.author | Hayball, J. | - |
dc.contributor.author | Lewis, I. | - |
dc.contributor.author | Brenner, M. | - |
dc.contributor.author | Brown, M. | - |
dc.date.issued | 2016 | - |
dc.identifier.citation | Molecular Therapy, 2016; 24(6):1135-1149 | - |
dc.identifier.issn | 1525-0016 | - |
dc.identifier.issn | 1525-0024 | - |
dc.identifier.uri | http://hdl.handle.net/2440/101586 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | 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 | - |
dc.language.iso | en | - |
dc.publisher | Nature Publishing Group | - |
dc.rights | © The American Society of Gene & Cell Therapy | - |
dc.subject | T-Lymphocytes | - |
dc.subject | Cell Line, Tumor | - |
dc.subject | Animals | - |
dc.subject | Humans | - |
dc.subject | Mice | - |
dc.subject | Melanoma | - |
dc.subject | Neoplasm Metastasis | - |
dc.subject | Gangliosides | - |
dc.subject | Receptors, Antigen, T-Cell | - |
dc.subject | Xenograft Model Antitumor Assays | - |
dc.subject | Lymphocyte Activation | - |
dc.subject | Cell Survival | - |
dc.subject | Antibodies, Monoclonal, Humanized | - |
dc.subject | Programmed Cell Death 1 Receptor | - |
dc.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 | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1038/mt.2016.63 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1010386 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Gargett, T. [0000-0003-3713-1373] | - |
dc.identifier.orcid | Hayball, J. [0000-0002-3089-4506] | - |
dc.identifier.orcid | Brown, M. [0000-0002-5796-1932] [0000-0002-6678-1407] | - |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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