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Depletion of Peripheral Macrophages and Brain Microglia Increases Brain Tumor Titers of Oncolytic Viruses

¹ Molecular Neuro-oncology Laboratories, Neurosurgery Service, and Center for Molecular Imaging, Massachusetts General Hospital, Charlestown, Massachusetts; ² Brain Tumor Research Center, Neurosurgery Service, and Departments of ³ Pathology, ⁴ Radiology, and ⁵ Neurology, Massachusetts General Hospital, Boston, Massachusetts; ⁶ Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, James Cancer Hospital/Solove Research Institute, ⁷ Division of Pharmaceutics, College of Pharmacy, and ⁸ Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio; ⁹ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia; and ¹⁰ Department of Cell Biology and Immunology, Vrije Universiteit, Amsterdam, the Netherlands

Requests for reprints: Giulia Fulci, Brain Tumor Research Center, Neurosurgery Department, Massachusetts General Hospital, Simches Research Building CRPZN 3800, 185 Cambridge Street, Boston, MA 02114. Phone: 617-643-3431; Fax: 617-643-3422; E-mail: gfulci{at}partners.org or E. Antonio Chiocca, Department of Neurological Surgery, The Ohio State University Medical Center, N-1017 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-9312; Fax: 614-293-4024; E-mail: EA.Chiocca{at}osumc.edu.

Clinical trials have proven oncolytic virotherapy to be safe but not effective. We have shown that oncolytic viruses (OV) injected into intracranial gliomas established in rodents are rapidly cleared, and this is associated with up-regulation of markers (CD68 and CD163) of cells of monocytic lineage (monocytes/microglia/macrophages). However, it is unclear whether these cells directly impede intratumoral persistence of OV through phagocytosis and whether they infiltrate the tumor from the blood or the brain parenchyma. To investigate this, we depleted phagocytes with clodronate liposomes (CL) in vivo through systemic delivery and ex vivo in brain slice models with gliomas. Interestingly, systemic CL depleted over 80% of peripheral CD163⁺ macrophages in animal spleen and peripheral blood, thereby decreasing intratumoral infiltration of these cells, but CD68⁺ cells were unchanged. Intratumoral viral titers increased 5-fold. In contrast, ex vivo CL depleted only CD68⁺ cells from brain slices, and intratumoral viral titers increased 10-fold. These data indicate that phagocytosis by both peripheral CD163⁺ and brain-resident CD68⁺ cells infiltrating tumor directly affects viral clearance from tumor. Thus, improved therapeutic efficacy may require modulation of these innate immune cells. In support of this new therapeutic paradigm, we observed intratumoral up-regulation of CD68⁺ and CD163⁺ cells following treatment with OV in a patient with glioblastoma. [Cancer Res 2007;67(19):9398–406]

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				Correction: Virus-Induced Phagocytes Impede Glioma Viral Therapy Cancer Res., November 15, 2007; 67(22): 11092 - 11092. [Full Text] [PDF]