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|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|
|Citation:||Molecular Therapy, 2016; 24(6):1135-1149|
|Publisher:||Nature Publishing Group|
|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; 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 Receptor|
|Rights:||© The American Society of Gene & Cell Therapy|
|Appears in Collections:||Medicine publications|
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