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|dc.identifier.citation||Cytotherapy, 2015; 17(4):487-495||en|
|dc.description.abstract||Background aims: Chimeric antigen receptor (CAR) T cells are a novel immunotherapy for cancer. To achieve anti-tumor efficacy, these cells must survive, expand, and persist after infusion into patients, functions that are reportedly best achieved by cells with a stem or central-memory rather than effector-memory phenotype. We have developed third-generation CAR T cells specific for the tumor-associated antigen GD2 for use in a phase I clinical trial. We investigated the optimal cell culture conditions for CAR T-cell production, and here we describe the relative effects of 3 activation and cytokine conditions on CAR T-cell expansion, effector function and phenotype. Methods: Peripheral blood mononuclear cells were activated by anti-CD3 and anti-CD28 or anti-CD3 and Retronectin. Activated cells were transduced with the CAR-encoding retroviral vector and expanded in either interleukin (IL)-2 or IL-7 and IL-15. Immune phenotype and expansion were tracked throughout the culture, and transduction efficiency, and subsequent GD2-specific effector functions were evaluated by flow cytometry and cytotoxic T lymphocytes assay. Results: CD3/Retronectin stimulation with IL-2 resulted in poorer activation, expansion and Th1 cytokine secretion of CAR T cells than CD3/CD28 stimulation with either IL-2 or IL-7 and IL-15. However, CAR T cells cultured in CD3/CD28/IL7/IL-15 and CD3/Retronectin/IL-2 had superior cytotoxic T lymphocyte activity and a more stem-like phenotype. Discussion: The combination of CD3 and CD28 with IL-7 and IL-15 gave the best balance of CAR T-cell expansion and potent GD2-specific effector functions while retaining a stem/memory phenotype, and these growth conditions will therefore be used to manufacture CAR T cells for our phase I clinical trial.||en|
|dc.description.statementofresponsibility||Tessa Gargett and Michael P. Brown||en|
|dc.rights||Crown Copyright © 2015 Published by Elsevier Inc. on behalf of International Society for Cellular Therapy. All rights reserved.||en|
|dc.subject||Anti-CD3 and anti-CD28 stimulation; chimeric antigen receptor T cells; effector function; IL-7; IL-15; IL-2; immune phenotype; Retronectin||en|
|dc.title||Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2||en|
|dc.identifier.orcid||Gargett, T. [0000-0003-3713-1373]||en|
|dc.identifier.orcid||Brown, M. [0000-0002-5796-1932]||en|
|Appears in Collections:||Medicine publications|
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