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Nat Commun ; 9(1): 785, 2018 03 06.
Article in English | MEDLINE | ID: mdl-29511178

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.


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