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Cancer Res. 2018 Jan 1;78(1):256-264. doi: 10.1158/0008-5472.CAN-17-0469. Epub 2017 Nov 1.

Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma.

Author information

1
Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.
2
The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.
3
Department of Pathology, Duke University Medical Center, Durham, North Carolina.
4
Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
5
Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
6
Department of Neurology, Duke University Medical Center, Durham, North Carolina.
7
Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina. john.sampson@duke.edu duane.mitchell@neurosurgery.ufl.edu.
#
Contributed equally

Abstract

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 DCs 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 IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated (R = 0.7371, P = 0.0369) 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.Significance: A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. Cancer Res; 78(1); 256-64. ©2017 AACR.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00693095.

PMID:
29093005
PMCID:
PMC5754236
DOI:
10.1158/0008-5472.CAN-17-0469
[Indexed for MEDLINE]
Free PMC Article

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