title: The efficacy of intracranial PLG-based vaccines is dependent on direct implantation into brain tissue.
abstract: We previously engineered a macroporous, polymer-based vaccine that initially produces GM-CSF gradients to recruit local dendritic cells and subsequently presents CpG oligonucleotides, and tumor lysate to cell infiltrates to induce immune cell activation and immunity against tumor cells in peripheral tumor models. Here, we demonstrate that this system eradicates established intracranial glioma following implantation into brain tissue, whereas implantation in resection cavities obviates vaccine efficacy. Rats bearing seven-day old, intracranial glioma tumors were treated with PLG vaccines implanted into the tumor bed, resulting in retention of contralateral forelimb function (day 17) that is compromised by tumor formation in control animals, and 90% long-term survival (>100 days). Similar benefits were observed in animals receiving tumor resection plus vaccine implants into the adjacent parenchyma, but direct implantation of PLG vaccines into the resection cavity conferred no benefit. This dissociation of efficacy was likely related to GM-CSF distribution, as implantation of PLG vaccines within brain tissue produced significant GM-CSF gradients for prolonged periods, which was not detected after implantation in resection cavities. These studies demonstrate that PLG vaccine efficacy is correlated to GM-CSF gradient formation, which requires direct implantation into brain tissue, and justify further exploration of this approach for glioma treatment.
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 02138, USA.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Ali
authors.forename: Edward
authors.initials: E
authors.lastname: Doherty
authors.forename: William J
authors.initials: WJ
authors.lastname: Bell
authors.forename: Tracie
authors.initials: T
authors.lastname: Fradet
authors.forename: Jebecka
authors.initials: J
authors.lastname: Hudak
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Laliberte
authors.forename: David J
authors.initials: DJ
authors.lastname: Mooney
authors.forename: Dwaine F
authors.initials: DF
authors.lastname: Emerich
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000627:therapeutic use; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000627:therapeutic use; D007167:Immunotherapy; D008297:Male; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000627:therapeutic use; D011098:Polyglactin 910 / Q000737:chemistry*; D016062:Porosity; D019736:Prostheses and Implants; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D009838:Oligodeoxyribonucleotides; D011098:Polyglactin 910; D016178:Granulocyte-Macrophage Colony-Stimulating Factor