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Primed tumor-reactive multifunctional CD62L+ human CD8+ T cells for immunotherapy

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Abstract

T cell-mediated immunotherapy against malignancies has been shown to be effective for certain types of cancer. However, ex vivo expansion of tumor-reactive T cells has been hindered by the low precursor frequency of such cells, often requiring multiple rounds of stimulation, resulting in full differentiation, loss of homing receptors and potential exhaustion of the expanded T cells. Here, we show that when using highly purified naïve CD8+ T cells, a single stimulation with peptide-pulsed, IFNγ/LPS-matured dendritic cells in combination with the sequential use of IL-21, IL-7 and IL-15 is sufficient for extensive expansion of antigen-specific T cells. Short-term expanded T cells were tumor-reactive, multifunctional and retained a central-memory-like phenotype (CD62L+, CCR7+, CD28+). The procedure is highly reproducible and robust as demonstrated for different healthy donors and for cancer patients. Such short-term tumor-antigen-primed, multifunctional T cells may therefore serve as a platform to target different malignancies accessible to immunotherapy.

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Acknowledgments

The authors would like to thank B. Bünting for help with the Immunoscope analysis and Prof. J. Becker (Department of Dermatology, Würzburg) and PD Dr. Vince and Dr. Hagemann (Department of Neurosurgery, Würzburg) for providing tumor cell lines. M.W. is the recipient of a post-doctoral stipend from the Child-Philipp-Foundation (T/237/16586/2007), Germany. This work was supported by the Parent’s Initiative Group for Children with Leukemia and Solid Tumors Würzburg and Main-Tauber e.V. as well as by a program project grant from BayImmuNet (to MW and PGS)(F2-F5121.7.1.1/13/1/2009). S.W.V.G. is supported by the Olivia Hendrickx Research Fund, the TBM program of the IWT-Flanders and a grant from the Belgian federation against cancer. P.D.G. was supported by grants from the National Institutes of Health (CA18029 and CA33084), the Leukemia and Lymphoma Society (LLS 7040–03), and the Bill and Melinda Gates Foundation.

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Correspondence to Matthias Wölfl.

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Wölfl, M., Merker, K., Morbach, H. et al. Primed tumor-reactive multifunctional CD62L+ human CD8+ T cells for immunotherapy. Cancer Immunol Immunother 60, 173–186 (2011). https://doi.org/10.1007/s00262-010-0928-8

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