Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/101586
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dc.contributor.authorGargett, T.en
dc.contributor.authorYu, W.en
dc.contributor.authorDotti, G.en
dc.contributor.authorYvon, E.en
dc.contributor.authorChristo, S.en
dc.contributor.authorHayball, J.en
dc.contributor.authorLewis, I.en
dc.contributor.authorBrenner, M.en
dc.contributor.authorBrown, M.en
dc.date.issued2016en
dc.identifier.citationMolecular Therapy, 2016; 24(6):1135-1149en
dc.identifier.issn1525-0016en
dc.identifier.issn1525-0024en
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.en
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 Brownen
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.rights© The American Society of Gene & Cell Therapyen
dc.subjectT-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 Receptoren
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 blockadeen
dc.typeJournal articleen
dc.identifier.rmid0030046615en
dc.identifier.doi10.1038/mt.2016.63en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1010386en
dc.identifier.pubid241923-
pubs.library.collectionMedicine publicationsen
pubs.library.teamDS10en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidGargett, T. [0000-0003-3713-1373]en
dc.identifier.orcidHayball, J. [0000-0002-3089-4506]en
dc.identifier.orcidBrown, M. [0000-0002-5796-1932]en
Appears in Collections:Medicine publications

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