Cytomegalovirus (CMV) is found in glioblastomas (GBM) and not in normal brain, but CMV-specific T cells from GBM patients prepared for adoptive transfer exhibit low polyfunctionality after in vitro expansion. In a pilot clinical trial, Reap et al. showed that co-administration of CMV RNA-loaded dendritic cells increased the frequency of polyfunctional CMV-specific CD8+ T cells, which also correlated with improved survival, although the study was not powered to conclude causality.

Median survival for glioblastoma (GBM) remains <15 months. Human Cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)-specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DC would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here we report prospective results of a pilot trial in which 22 patients with newly-diagnosed GBM were initially enrolled of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-Saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNgamma+, TNFalpha+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.

Author Info: (1) Neurosurgery, Duke University. (2) Pathology, Duke University. (3) Neurosurgery, Duke University Medical Center. (4) Department of Neurosurgery, Duke. (5) Neurosurgery, Duke Un

Author Info: (1) Neurosurgery, Duke University. (2) Pathology, Duke University. (3) Neurosurgery, Duke University Medical Center. (4) Department of Neurosurgery, Duke. (5) Neurosurgery, Duke University Medical Center. (6) Division of Neurosurgery, Duke University Medical Center. (7) Department of Neurosurgery, Duke University. (8) Biostatistics, Duke University Medical Center. (9) Divisions of Medical Oncology and Urology, Duke University, Duke Cancer Institute. (10) Neurosurgery, Duke University. (11) Neurosurgery, Duke University Medical Center. (12) Neurosurgery, Duke University. (13) Department of Neurosurgery, Duke University. (14) Biomedical Engineering, Duke University. (15) Surgery, Duke University Medical Center. (16) Neurosurgery, Duke University. (17) Neurosurgery, Duke University. (18) Surgery, Duke University. (19) Neurosurgery, Duke University. (20) Neurosurgery, Duke University. (21) Surgery, Duke University Medical Center. (22) The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center. (23) Neurosurgery, Duke University. (24) Neurosurgery, Duke University. (25) Department of Surgery, Duke University Medical Center. (26) Division of Neurosurgery, Duke University Medical Center. (27) Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center at Duke. (28) Division of Neurosurgery, Department of Surgery, Duke University Medical Center. (29) Neurosurgery, University of Florida. (30) Neurosurgery, Duke University Medical Center john.sampson@duke.edu.