Abstract 4749: Genetic signature of malignant glioma is associated with responsiveness to autologous tumor lysate-pulsed dendritic cell vaccination + TLR agonists

Abstract

Abstract Purpose: We previously reported that the toll-like receptor (TLR)-7 agonist, imiquimod, could enhance dendritic cell activation and migration, as well as stimulate T cell-mediated anti-tumor immune responses in a murine glioma model. To translate these findings, a Phase I clinical trial was initiated to evaluate this strategy for its feasibility, safety, and induction of immune responses in patients with malignant glioma. Herein, we report the results of this phase I, dose escalation clinical trial using autologous tumor lysate-pulsed dendritic cell (DC) vaccination, supplemented with the toll-like receptor agonists, imiquimod or poly ICLC, for patients with malignant glioma. Patients and Methods: Twenty-two glioblastoma patients (15 newly diagnosed, 7 recurrent) were enrolled into a multi-cohort dose-escalation study and treated with 1, 5, or 10 million autologous DC pulsed with tumor lysate. Three biweekly intradermal vaccinations were initially administered. Subsequently, patients received booster vaccinations together with imiquimod or poly ICLC every three months until tumor progression or lysate was depleted. Patients were monitored for adverse events, survival, and immune responses. For patients with available pre-treatment tumor and/or PBMC, microarray-based hierarchical clustering, lymphocyte immunohistochemistry, FACS and cytokine bead arrays were performed for monitoring purposes. Results: DC vaccinations were not associated with any evidence of dose-limiting toxicity or serious adverse effects. The median survival was 35 months for newly diagnosed patients and 11 months for recurrent patients, but still increasing as several patients are still alive at this point. Typical glioblastoma gene expression signatures, previously characterized by our group, were found. Contrary to our previous reports, however, patients with proliferative (Pro) or mesenchymal (Mes) signatures exhibited prolonged survival, while patients with pro-neural (PN) signatures did not. Pre-treatment Pro, Mes or Pro/Mes tumor sections had increased CD3 and CD8 positive cells within the tumor compared with PN tumor sections. Conclusions: Pro, Mes or Pro/Mes gene expression signatures may identify patients with pre-existing immunity and who may benefit from immune-based vaccination studies. However, prospective studies will need to be performed to establish the validity of these findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4749.