RESUMEN
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.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Neoplasias Encefálicas/terapia , Glioblastoma/inmunología , Glioblastoma/terapia , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Células Presentadoras de Antígenos/trasplante , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , ADN/genética , ADN/inmunología , Metilación de ADN , Femenino , Glioblastoma/genética , Humanos , Inmunoterapia Adoptiva , Masculino , Estudios Prospectivos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/trasplante , Linfocitos T Colaboradores-Inductores/trasplante , Adulto JovenRESUMEN
BACKGROUND: Cytokines play an integral role in the coordination and persistence of allergic inflammatory processes and therefore represent prime targets for novel therapies in diseases such as asthma. Multiple attempts to generate low-molecular-weight cytokine inhibitors have failed, and the main attention has focused on the development of biological agents such as neutralizing antibodies. The present work describes a simple and effective method to induce the production of therapeutic anti-cytokine autoantibodies by active immunization against a modified endogenous cytokine. METHODS: Balb/c mice were subcutaneously injected with AutoVac TNF106, a recombinant murine TNF-alpha molecule containing a foreign immunogenic T helper epitope, and the induction of neutralizing anti-TNF-alpha autoantibodies was analysed. These mice were then sensitized with ovalbumin (OVA), and the effect of neutralizing anti-TNF-alpha autoantibodies on the allergen-induced airway inflammation was analysed. RESULTS: AutoVac TNF106-immunized mice developed high titres of neutralizing anti-TNF-alpha autoantibodies, which were maintained for at least 4 weeks after the last booster injection. Mice vaccinated with AutoVac TNF106 and further immunized against OVA showed diminished TNF-alpha levels in the bronchoalveolar lavage (BAL) fluid after OVA challenge. Moreover, pretreatment with AutoVac TNF106 resulted in significantly reduced numbers of eosinophils and neutrophils in BAL fluid in response to single or multiple allergen exposure. CONCLUSION: The induction of anti-TNF-alpha autoantibody production by the AutoVac TNF106 technology not only confirmed the role of TNF-alpha in the induction of allergic inflammation but also offers a novel approach to block the activity of cytokines in order to treat allergic inflammatory conditions.