Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/101586
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dc.contributor.authorGargett, T.-
dc.contributor.authorYu, W.-
dc.contributor.authorDotti, G.-
dc.contributor.authorYvon, E.-
dc.contributor.authorChristo, S.-
dc.contributor.authorHayball, J.-
dc.contributor.authorLewis, I.-
dc.contributor.authorBrenner, M.-
dc.contributor.authorBrown, M.-
dc.date.issued2016-
dc.identifier.citationMolecular Therapy, 2016; 24(6):1135-1149-
dc.identifier.issn1525-0016-
dc.identifier.issn1525-0024-
dc.identifier.urihttp://hdl.handle.net/2440/101586-
dc.description.abstractChimeric 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.statementofresponsibilityTessa 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.isoen-
dc.publisherNature Publishing Group-
dc.rights© The American Society of Gene & Cell Therapy-
dc.subjectT-Lymphocytes-
dc.subjectCell Line, Tumor-
dc.subjectAnimals-
dc.subjectHumans-
dc.subjectMice-
dc.subjectMelanoma-
dc.subjectNeoplasm Metastasis-
dc.subjectGangliosides-
dc.subjectReceptors, Antigen, T-Cell-
dc.subjectXenograft Model Antitumor Assays-
dc.subjectLymphocyte Activation-
dc.subjectCell Survival-
dc.subjectAntibodies, Monoclonal, Humanized-
dc.subjectProgrammed Cell Death 1 Receptor-
dc.titleGD2-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.typeJournal article-
dc.identifier.doi10.1038/mt.2016.63-
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1010386-
pubs.publication-statusPublished-
dc.identifier.orcidGargett, T. [0000-0003-3713-1373]-
dc.identifier.orcidHayball, J. [0000-0002-3089-4506]-
dc.identifier.orcidBrown, M. [0000-0002-5796-1932] [0000-0002-6678-1407]-
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