Human cytomegalovirus (CMV) antigens have been shown by ten independent laboratories to be expressed in a high proportion of malignant gliomas. We have recently completed a phase I clinical trial exploring the safety, immunogenicity, and potential clinical efficacy of autologous pp65 RNA pulsed DC vaccines in patients with newly- diagnosed GBM. This trial explored the capacity to enhance DC migration to vaccine-site draining lymph nodes (VDLNs) using inflammatory skin preparations administered prior to pp65 RNA-loaded DC vaccines in a randomized pilot trial design (n=12 patients). The results of these studies demonstrated the capacity to safely expand CMV-specific cellular and humoral immunity in patients with GBM using autologous RNA-pulsed DC vaccines and demonstrated a strong correlation with successful DC migration to VDLNs and clinical outcomes (R=0.73, P=0.007; Pearson correlation coefficient). Strikingly, patients randomized to receive a tetanus toxoid booster as an inflammatory stimulus at the vaccine-site showed an increased migration of DCs to VDLNs (P=0.04) and a corresponding increased progression-free and overall survival (P=0.01 Logrank analysis). These results suggested that successful DC trafficking in vivo is associated with improved outcomes in patients with GBM receiving pp65 RNA-pulsed DC vaccines and that inflammatory stimuli that enhance DC migration improve the efficacy of this treatment modality. In support of this hypothesis, we found increased levels of chemokines that facilitate DC migration in patients randomized to the tetanus group. Additionally, we have corroborated these findings using a transgenic mouse model employing GFP+ mice to evaluate DC migration. Pp65 RNA-pulsed DCs are a novel and promising therapeutic modality for patients with GBM, and our studies indicate that DC migration to VDLNs constitutes a major biological axis for potential clinical intervention in order to enhance the efficacy of this treatment strategy. In this proposal, we aim to prospectively validate DC migration as a functional biomarker for survival outcomes in a randomized, double-blinded phase 2 clinical trial, and identify serologic mediators of DC migratory activity. Project Description Page 6
The significance of this research is that it may advance a new therapy for malignant brain tumors as well as provide a strategy for treatment that can be applied to many other cancers. Improved therapy for cancer has significant potential to improve public health and quality of life for patients affected by malignant disease.
|Batich, Kristen A; Reap, Elizabeth A; Archer, Gary E et al. (2017) Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination. Clin Cancer Res 23:1898-1909|
|Sayour, Elias J; Mitchell, Duane A (2017) Immunotherapy for Pediatric Brain Tumors. Brain Sci 7:|