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

Autor:	Batich KA; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina., Reap EA; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina., Archer GE; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Sanchez-Perez L; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina., Nair SK; Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina., Schmittling RJ; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina., Norberg P; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina., Xie W; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina., Herndon JE 2nd; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina., Healy P; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina., McLendon RE; Department of Pathology, Duke University Medical Center, Durham, North Carolina.; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Friedman AH; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Friedman HS; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Bigner D; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina.; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Vlahovic G; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Mitchell DA; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina. john.sampson@duke.edu duane.mitchell@neurosurgery.ufl.edu.; Department of Pathology, Duke University Medical Center, Durham, North Carolina.; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Sampson JH; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina. john.sampson@duke.edu duane.mitchell@neurosurgery.ufl.edu.; Department of Pathology, Duke University Medical Center, Durham, North Carolina.; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Immunology, Duke University Medical Center, Durham, North Carolina.; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Apr 15; Vol. 23 (8), pp. 1898-1909.
DOI:	10.1158/1078-0432.CCR-16-2057
Abstrakt:	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/m 2 /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 . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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