Abstract
Glioblastoma (GBM) is among the most invasive and lethal of cancers, frequently infiltrating surrounding healthy tissue and giving rise to rapid recurrence. It is therefore critical to establish experimental model systems and develop therapeutic approaches that enhance anti-tumor immunity. In the current study, we have employed a newly developed murine glioma model to assess the efficacy of a novel picornavirus vaccination approach for the treatment of established tumors. The GL261-Quad system is a variation of the GL261 syngeneic glioma that has been engineered to expresses model T cell epitopes including OVA257–264. MRI revealed that both GL261 and GL261-Quad tumors display characteristic features of human gliomas such as heterogeneous gadolinium leakage and larger T2 weighted volumes. Analysis of brain-infiltrating immune cells demonstrated that GL261-Quad gliomas generate detectable CD8+ T cell responses toward the tumor-specific Kb:OVA257–264 antigen. Enhancing this response via a single intracranial or peripheral vaccination with picornavirus expressing the OVA257–264 antigen increased anti-tumor CD8+ T cells infiltrating the brain, attenuated progression of established tumors, and extended survival of treated mice. Importantly, the efficacy of the picornavirus vaccination is dependent on functional cytotoxic activity of CD8+ T cells, as the beneficial response was completely abrogated in mice lacking perforin expression. Therefore, we have developed a novel system for evaluating mechanisms of anti-tumor immunity in vivo, incorporating the GL261-Quad model, 3D volumetric MRI, and picornavirus vaccination to enhance tumor-specific cytotoxic CD8+ T cell responses and track their effectiveness at eradicating established gliomas in vivo.
Highlights
Glioblastoma (GBM) is among the most lethal of cancers, with a median survival of less than 15 months post-diagnosis despite aggressive, multi-modal treatment[1]
Vaccination with autologous tumor lysate-pulsed dendritic cells (DC) and tolllike receptor (TLR) agonists in a phase I clinical trial resulted in the enhancement of tumor-infiltrating CD8+ T cells and increased survival among a subset of patients[3]
GL261-Quad tumor sizes as determined by bioluminescence imaging (BLI) showed a strong correlation with both T1 gadolinium-enhanced (R2 = 0.9296) and T2 weighted (R2 = 0.9045) MRI, validating the MR imaging parameters and confirming maintained luciferase doi:10.1371/journal.pone.0125565.g001
Summary
Glioblastoma (GBM) is among the most lethal of cancers, with a median survival of less than 15 months post-diagnosis despite aggressive, multi-modal treatment[1]. Vaccination with autologous tumor lysate-pulsed dendritic cells (DC) and tolllike receptor (TLR) agonists in a phase I clinical trial resulted in the enhancement of tumor-infiltrating CD8+ T cells and increased survival among a subset of patients[3]. A phase II clinical trial using autologous tumor lysate-pulsed DCs demonstrated a logarithmic correlation between clinical outcome and the magnitude of T cell responses, as measured by IFN-γ production[7]. The results of these studies demonstrate the potential of immunotherapeutic approaches aimed at promoting CD8+ T cell responses in improving outcomes for glioma patients
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