To generate tumor-reactive lymphocytes, Kirkin et al. used genome demethylation to induce the expression of cancer/testis (CT) antigens on autologous CD4+ Th cells, which acted as APCs when incubated with patient’s peripheral blood lymphocytes, resulting in CD8+ T cells and NK cells exhibiting early differentiation state markers. In a phase I clinical trial of 25 patients with late-stage glioblastoma, injection of these cytotoxic lymphocytes was safe, demonstrated homing to tumor, and led to tumor regression in multiple patients.
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.
