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 and Walter Fischer
Additional contact information
Alexei F. Kirkin: Danish Cancer Society Research Center
Karine N. Dzhandzhugazyan: Danish Cancer Society Research Center
Per Guldberg: Danish Cancer Society Research Center
Johnny Jon Fang: Danish Cancer Society Research Center
Rikke S. Andersen: University of Southern Denmark
Christina Dahl: Danish Cancer Society Research Center
Jann Mortensen: Copenhagen University Hospital
Tim Lundby: Copenhagen University Hospital
Aase Wagner: Copenhagen University Hospital
Ian Law: Copenhagen University Hospital
Helle Broholm: Copenhagen University Hospital
Line Madsen: Aarhus University Hospital
Christer Lundell-Ek: CytoVac A/S
Morten F. Gjerstorff: University of Southern Denmark
Henrik J. Ditzel: University of Southern Denmark
Martin R. Jensen: CytoVac A/S
Walter Fischer: CytoVac A/S

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03217-9

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