Despite aggressive chemotherapy, surgical resection, and radiation therapy, glioblastoma (GBM) remains almost universally fatal. A recent randomized, control trial demonstrated RNA-loaded dendritic cell (DC) vaccines significantly prolong overall and progression free survival in patients with primary GBM. Moreover, this trial also demonstrated that dendritic cell migration to lymph nodes could be used a clinically meaningful predictor of patient response to treatment. This technique provides researchers a surrogate endpoint to develop enhanced dendritic cell vaccine protocols and could provide clinicians with a powerful tool to predict patient response to treatment just 48 hours after vaccination. However, the high regulatory requirements associated with standard methods of tracking cell migration limit future application of this technique. This project is designed to evaluate use of theranostic RNA-loaded nanoparticles (RNA-NPs) to enhance and track DC migration to LNs. Preliminary evidence indicates that RNA-NPs 1) stimulate potent DC activation 2) enhance DC migration to LNs, and 3) can be loaded with sufficient levels of iron oxide to be tracked with MRI. This study will test the hypothesis that RNA-NPs can be used to enhance DC migration to LNs, predict vaccine efficacy with MRI, and improve antitumor immune responses. These goals will be assessed with the following Specific Aims:
Aim 1 : Determine effects of RNA-NP loading on dendritic cell activation and migration to LNs Unique benefits of RNA-NP loading on DC activation will be assessed with genomic analysis of intracellular signaling pathways. Functional consequences of RNA-NP loading will be determined in a murine model of our vaccine protocol.
Aim 2 : Determine predictive utility of MRI-detected dendritic cell migration The sensitivity of MRI based detection of RNA-NP loaded DCs will be determined by correlating changes in MRI intensity to absolute counts of RNA-NP-loaded DsRed+ DCs in lymph nodes. The predictive value of MRI- detected DC migration will then be assessed in a murine glioma model.
Aim 3 : Evaluate efficacy of RNA-NP loaded dendritic cells in a murine model of GBM Mice will be vaccinated with RNA-NP-loaded DCs. Antigen specific T cell activation will be assessed with a T cell killing assay. Survival benefit over other DC preparation methods will be assessed in an aggressive temozolomide and radiation resistant murine model of high grade glioma. Significance This project promises to produce a powerful tool to enhance and predict long term survival in patients with GBM. The combination of a readily accessible imaging component with a robustly stimulatory nanoparticle formulation would allow streamlined manufacturing of a low cost, theranostic nanoparticle that would provide clinicians an unprecedented advantage in patient management.
Malignant brain tumors are the leading cause of cancer related death in children and a major cause of morbidity and mortality in adults due to resistance to conventional therapies. Dendritic cell vaccines have induced profound antitumor responses in patients with glioblastoma but are only effective for a subset of patients. This project seeks to improve dendritic cell vaccines for treatment of malignant brain tumors and provide clinicians with a tool to predict which patients will respond to treatment.
