title: Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses.
abstract: 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.
authors.affiliation: Molecular Neuro-oncology Laboratories, Neurosurgery Service, and Center for Molecular Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, USA. gfulci@partners.org
authors.forename: Giulia
authors.initials: G
authors.lastname: Fulci
authors.forename: Nina
authors.initials: N
authors.lastname: Dmitrieva
authors.forename: Davide
authors.initials: D
authors.lastname: Gianni
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Fontana
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Pan
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Lu
authors.forename: Claire S
authors.initials: CS
authors.lastname: Kaufman
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Sean E
authors.initials: SE
authors.lastname: Lawler
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Clay B
authors.initials: CB
authors.lastname: Marsh
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Anat O
authors.initials: AO
authors.lastname: Stemmer-Rachamimov
authors.forename: Anat Stemmer
authors.initials: AS
authors.lastname: Rachamimov
authors.forename: Fred H
authors.initials: FH
authors.lastname: Hochberg
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martuza
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000097:blood / Q000473:pathology / Q000628:therapy / Q000821:virology*; D005910:Glioma / Q000097:blood / Q000473:pathology / Q000628:therapy / Q000821:virology*; D008264:Macrophages / Q000821:virology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017628:Microglia / Q000473:pathology; D050130:Oncolytic Virotherapy / Q000379:methods*; D010587:Phagocytosis; D051381:Rats; D011916:Rats, Inbred F344