Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells

Alexei F. Kirkin*, Karine N. Dzhandzhugazyan, Per Guldberg, Johnny Jon Fang, Rikke S. Andersen, Christina Dahl, Jann Mortensen, Tim Lundby, Aase Wagner, Ian Law, Helle Broholm, Line Madsen, Christer Lundell-Ek, Morten F. Gjerstorff, Henrik J. Ditzel, Martin R. Jensen, Walter Fischer

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Abstrakt

In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens. In a phase 1 trial of 25 patients with recurrent glioblastoma multiforme, cytotoxic lymphocytes homed to the tumor, with tumor regression ongoing in three patients for 14, 22, and 27 months, respectively. No treatment-related adverse effects were observed. This proof-of-principle study shows that tumor-reactive effector cells can be generated ex vivo by exposure to antigens induced by DNA demethylation, providing a novel, minimally invasive therapeutic strategy for treating cancer.

OriginalsprogEngelsk
Artikelnummer785
TidsskriftNature Communications
Vol/bind9
Antal sider12
ISSN2041-1723
DOI
StatusUdgivet - 6. mar. 2018

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  • Citationsformater

    Kirkin, A. F., Dzhandzhugazyan, K. N., Guldberg, P., Fang, J. J., Andersen, R. S., Dahl, C., Mortensen, J., Lundby, T., Wagner, A., Law, I., Broholm, H., Madsen, L., Lundell-Ek, C., Gjerstorff, M. F., Ditzel, H. J., Jensen, M. R., & Fischer, W. (2018). Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells. Nature Communications, 9, [785]. https://doi.org/10.1038/s41467-018-03217-9