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

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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.

Original languageEnglish
JournalNature Communications
Volume9
Issue number1
Pages (from-to)785
ISSN2041-1723
DOIs
Publication statusPublished - 6 Mar 2018

    Research areas

  • Adult, Antigen-Presenting Cells/immunology, Antigens, Neoplasm/genetics, Brain Neoplasms/genetics, DNA/genetics, DNA Methylation, Female, Glioblastoma/genetics, Humans, Immunotherapy, Adoptive, Male, Prospective Studies, T-Lymphocytes, Cytotoxic/immunology, T-Lymphocytes, Helper-Inducer/immunology, Young Adult

ID: 55350890