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Oncoimmunology. 2015 Jan 22;4(3):e994374. eCollection 2015 Mar.

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas.

Author information

1
UF Brain Tumor Immunotherapy Program; Preston A. Wells, Jr. Center for Brain Tumor Therapy; Department of Neurosurgery; University of Florida ; Gainesville, FL, USA.
2
Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA.
3
Department of Pathology; Duke University Medical Center ; Durham, NC, USA.
4
Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA ; Department of Pathology; Duke University Medical Center ; Durham, NC, USA.

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.

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

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