Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells.
Kirkin AF, Dzhandzhugazyan KN, Guldberg P, Fang JJ, Andersen RS, Dahl C, Mortensen J, Lundby T, Wagner A, Law I, Broholm H, Madsen L, Lundell-Ek C, Gjerstorff MF, Ditzel HJ, Jensen MR, Fischer W
Nature Commun. 9(1):785
2018
Show 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. | 29511178
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