Gargett, T.Yu, W.Dotti, G.Yvon, E.Christo, S.Hayball, J.Lewis, I.Brenner, M.Brown, M.2016-10-052016-10-052016Molecular Therapy, 2016; 24(6):1135-11491525-00161525-0024http://hdl.handle.net/2440/101586Chimeric 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© The American Society of Gene & Cell TherapyT-LymphocytesCell Line, TumorAnimalsHumansMiceMelanomaNeoplasm MetastasisGangliosidesReceptors, Antigen, T-CellXenograft Model Antitumor AssaysLymphocyte ActivationCell SurvivalAntibodies, Monoclonal, HumanizedProgrammed Cell Death 1 ReceptorJournal article003004661510.1038/mt.2016.630003782800000152-s2.0-84964317521241923Gargett, T. [0000-0003-3713-1373]Hayball, J. [0000-0002-3089-4506]Brown, M. [0000-0002-5796-1932] [0000-0002-6678-1407]