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Clin Cancer Res. 2017 Apr 15;23(8):1898-1909. doi: 10.1158/1078-0432.CCR-16-2057.

Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination.

Author information

1
Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.
2
Department of Pathology, Duke University Medical Center, Durham, North Carolina.
3
Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.
4
Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
5
Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
6
Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina. john.sampson@duke.edu duane.mitchell@neurosurgery.ufl.edu.
7
Department of Immunology, Duke University Medical Center, Durham, North Carolina.
8
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Abstract

Purpose: Patients with glioblastoma have less than 15-month median survival despite surgical resection, high-dose radiation, and chemotherapy with temozolomide. We previously demonstrated that targeting cytomegalovirus pp65 using dendritic cells (DC) can extend survival and, in a separate study, that dose-intensified temozolomide (DI-TMZ) and adjuvant granulocyte macrophage colony-stimulating factor (GM-CSF) potentiate tumor-specific immune responses in patients with glioblastoma. Here, we evaluated pp65-specific cellular responses following DI-TMZ with pp65-DCs and determined the effects on long-term progression-free survival (PFS) and overall survival (OS).Experimental Design: Following standard-of-care, 11 patients with newly diagnosed glioblastoma received DI-TMZ (100 mg/m2/d × 21 days per cycle) with at least three vaccines of pp65 lysosome-associated membrane glycoprotein mRNA-pulsed DCs admixed with GM-CSF on day 23 ± 1 of each cycle. Thereafter, monthly DI-TMZ cycles and pp65-DCs were continued if patients had not progressed.Results: Following DI-TMZ cycle 1 and three doses of pp65-DCs, pp65 cellular responses significantly increased. After DI-TMZ, both the proportion and proliferation of regulatory T cells (Tregs) increased and remained elevated with serial DI-TMZ cycles. Median PFS and OS were 25.3 months [95% confidence interval (CI), 11.0-∞] and 41.1 months (95% CI, 21.6-∞), exceeding survival using recursive partitioning analysis and matched historical controls. Four patients remained progression-free at 59 to 64 months from diagnosis. No known prognostic factors [age, Karnofsky performance status (KPS), IDH-1/2 mutation, and MGMT promoter methylation] predicted more favorable outcomes for the patients in this cohort.Conclusions: Despite increased Treg proportions following DI-TMZ, patients receiving pp65-DCs showed long-term PFS and OS, confirming prior studies targeting cytomegalovirus in glioblastoma. Clin Cancer Res; 23(8); 1898-909. ©2017 AACR.

PMID:
28411277
PMCID:
PMC5559300
DOI:
10.1158/1078-0432.CCR-16-2057
[Indexed for MEDLINE]
Free PMC Article

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