title: Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas.
abstract: Adoptive cellular therapy (ACT) after lymphodepletive conditioning can induce dramatic clinical responses, but this approach has been largely limited to melanoma due to a lack of reliable methods for expanding tumor-specific lymphocytes from the majority of other solid cancers. We have employed tumor RNA-pulsed dendritic cells (DCs) to reliably expand CD4+and CD8+tumor-reactive T lymphocytes for curative ACT in a highly-invasive, chemotherapy- and radiation-resistant malignant glioma model. Curative treatment of established intracranial tumors involved a synergistic interaction between myeloablative (MA) conditioning, adoptively transferred tumor-specific T cells, and tumor RNA-pulsed DC vaccines. Hematopoietic stem cells (HSCs), administered for salvage from MA conditioning, rapidly migrated to areas of intracranial tumor growth and facilitated the recruitment of tumor-specific lymphocytes through HSC-elaborated chemokines and enhanced immunologic rejection of intracranial tumors during ACT. Furthermore, HSC transplant under non-myeloablative (NMA) conditions also enhanced immunologic tumor rejection, indicating a novel role for the use of HSCs in the immunologic treatment of malignant gliomas and possibly other solid tumors.
authors.affiliation: UF Brain Tumor Immunotherapy Program; Preston A. Wells, Jr. Center for Brain Tumor Therapy; Department of Neurosurgery; University of Florida ; Gainesville, FL, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Flores
authors.affiliation: UF Brain Tumor Immunotherapy Program; Preston A. Wells, Jr. Center for Brain Tumor Therapy; Department of Neurosurgery; University of Florida ; Gainesville, FL, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Pham
authors.affiliation: Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA.
authors.forename: David
authors.initials: D
authors.lastname: Snyder
authors.affiliation: Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA.
authors.forename: Shicheng
authors.initials: S
authors.lastname: Yang
authors.affiliation: Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Perez
authors.affiliation: UF Brain Tumor Immunotherapy Program; Preston A. Wells, Jr. Center for Brain Tumor Therapy; Department of Neurosurgery; University of Florida ; Gainesville, FL, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Sayour
authors.affiliation: Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA.
authors.forename: Xiuyu
authors.initials: X
authors.lastname: Cui
authors.affiliation: Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kemeny
authors.affiliation: Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Friedman
authors.affiliation: Department of Pathology; Duke University Medical Center ; Durham, NC, USA.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA ; Department of Pathology; Duke University Medical Center ; Durham, NC, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sampson
authors.affiliation: UF Brain Tumor Immunotherapy Program; Preston A. Wells, Jr. Center for Brain Tumor Therapy; Department of Neurosurgery; University of Florida ; Gainesville, FL, USA.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Mitchell
keywords: ACT, adoptive cellular therapy; CAR, chimeric antigen receptor; CBA, cytokine bead array; CCL3, (MIP1α) macrophage inhibitory protein 1; CXCL12, (SDF1) stromal derived factor 1; DC, dendritic cell; FACS, fluorescence activated cell sorting; GBM; HSC, haematopoietic stem cell; IFNγ, interferon gamma; IL-15, interleukin 15; IL-7, interleukin 7; MA, myeloablative; NMA, non-myeloablative; OVA, ovalbumin; SEM, standard error of mean; TAA, tumor associated antigens; TCR, T cell receptor; TMZ, temozolomide; TNFα, tumor necrosis factor α; TTRNA-T cells, tumor-specific T cells activated ex vivo using RNA-pulsed DCs; WBI, whole brain irradiation.; cellular therapy; glioblastoma; glioma; hematopoietic stem cells; immunotherapy