Abstract
PurposeDendritic cell (DC) vaccines have recently emerged as an innovative therapeutic option for glioblastoma patients. To identify novel surrogates of anti-tumor immune responsiveness, we studied the dynamic expression of activation and inhibitory markers on peripheral blood lymphocyte (PBL) subsets in glioblastoma patients treated with DC vaccination at UCLA.Experimental DesignPre-treatment and post-treatment PBL from 24 patients enrolled in two Phase I clinical trials of dendritic cell immunotherapy were stained and analyzed using flow cytometry. A univariate Cox proportional hazards model was utilized to investigate the association between continuous immune monitoring variables and survival. Finally, the immune monitoring variables were dichotomized and a recursive partitioning survival tree was built to obtain cut-off values predictive of survival.ResultsThe change in regulatory T cell (CD3+CD4+CD25+CD127low) frequency in PBL was significantly associated with survival (p = 0.0228; hazard ratio = 3.623) after DC vaccination. Furthermore, the dynamic expression of the negative co-stimulatory molecule, CTLA-4, was also significantly associated with survival on CD3+CD4+ T cells (p = 0.0191; hazard ratio = 2.840) and CD3+CD8+ T cells (p = 0.0273; hazard ratio = 2.690), while that of activation markers (CD25, CD69) was not. Finally, a recursive partitioning tree algorithm was utilized to dichotomize the post/pre fold change immune monitoring variables. The resultant cut-off values from these immune monitoring variables could effectively segregate these patients into groups with significantly different overall survival curves.ConclusionsOur results suggest that monitoring the change in regulatory T cell frequencies and dynamic expression of the negative co-stimulatory molecules on peripheral blood T cells, before and after DC vaccination, may predict survival. The cut-off point generated from these data can be utilized in future prospective immunotherapy trials to further evaluate its predictive validity.
Highlights
Glioblastoma is one of the most lethal of human cancers, with very few long-term survivors and no definitive cures for this disease
The change in regulatory T cell (CD3+CD4+CD25+CD127low) frequency in peripheral blood lymphocyte (PBL) was significantly associated with survival (p = 0.0228; hazard ratio = 3.623) after dendritic cells (DC) vaccination
Our results suggest that monitoring the change in regulatory T cell frequencies and dynamic expression of the negative co-stimulatory molecules on peripheral blood T cells, before and after DC vaccination, may predict survival
Summary
Glioblastoma is one of the most lethal of human cancers, with very few long-term survivors and no definitive cures for this disease These tumors invade and infiltrate the surrounding brain, making complete surgical excision impossible. Immunotherapy is theoretically appealing because it offers the potential for a high degree of tumor-specificity, while sparing normal brain structures [10]. One such approach uses professional antigen-presenting cells, known as dendritic cells (DC), co-cultured with autologous tumor lysate or glioma-associated antigens to target these tumors immunologically. Initial studies of DC-based vaccine therapy for malignant gliomas have shown acceptable safety and toxicity profiles [11,12,13,14,15,16,17,18,19,20,21,22], and multi-center randomized Phase II and III studies are currently underway
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call