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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 4/2013

01-04-2013 | Original article

Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails

Authors: Shicheng Yang, Yun Ji, Luca Gattinoni, Ling Zhang, Zhiya Yu, Nicholas P. Restifo, Steven A. Rosenberg, Richard A. Morgan

Published in: Cancer Immunology, Immunotherapy | Issue 4/2013

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Abstract

The genetic modification of CD8+ T cells using anti-tumor T-cell receptors (TCR) or chimeric antigen receptors is a promising approach for the adoptive cell therapy of patients with cancer. We previously developed a simplified method for the clinical-scale generation of central memory-like (Tcm) CD8+ T cells following transduction with lentivirus encoding anti-tumor TCR and culture in the presence of IL-2. In this study, we compared different cytokines or combinations of IL-2, IL-7, IL-12, IL-15, and IL-21 to expand genetically engineered CD8+ T cells. We demonstrated that specific cytokine combinations IL-12 plus IL-7 or IL-21 for 3 days followed by withdrawal of IL-12 yielded the phenotype of CD62LhighCD28high CD127highCD27highCCR7high, which is associated with less-differentiated T cells. Genes associated with stem cells (SOX2, NANOG, OCT4, and LIN28A), were also up-regulated by this cytokine cocktail. Moreover, the use of IL-12 plus IL-7 or IL-21 yielded CD8 T cells showing enhanced persistence in the NOD/SCID/γc−/− mouse model. This defined cytokine combination could also alter highly differentiated TIL from melanoma patients into cells with a less-differentiated phenotype. The methodology that we developed for generating a less-differentiated anti-tumor CD8+ T cells ex vivo may be ideal for the adoptive immunotherapy of cancer.
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Metadata
Title
Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails
Authors
Shicheng Yang
Yun Ji
Luca Gattinoni
Ling Zhang
Zhiya Yu
Nicholas P. Restifo
Steven A. Rosenberg
Richard A. Morgan
Publication date
01-04-2013
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 4/2013
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-012-1378-2

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