title: Targeted liposomal delivery of TLR9 ligands activates spontaneous antitumor immunity in an autochthonous cancer model.
abstract: Accessibility of tumors for highly effective local treatment represents a major challenge for anticancer therapy. Immunostimulatory oligodeoxynucleotides (ODN) with CpG motifs are ligands of TLR9, which prime spontaneous antitumor immunity, but are less effective when applied systemically. We therefore developed a liposome-based agent for selective delivery of CpG-ODN into the tumor environment. A peptide that specifically targets angiogenic endothelial cells in a transgenic tumor model for islet cell carcinogenesis was engrafted into CpG-ODN containing liposomes. Intravenous injection of these liposomes resulted in specific accumulation around tumor vessels, increased uptake by tumor-resident macrophages, and retention over time. In contrast, nontargeted liposomes did not localize to the tumor vasculature. Consequently, only vascular targeting of CpG-ODN liposomes provoked a marked inflammatory response at vessel walls with enhanced CD8(+) and CD4(+) T cell infiltration and, importantly, activation of spontaneous, tumor-specific cytotoxicity. In a therapeutic setting, 40% of tumor-bearing, transgenic mice survived beyond week 45 after systemic administration of vascular-directed CpG-ODN liposomes. In contrast, control mice survived up to 30 wk. Therapeutic efficacy was further improved by increasing the frequency of tumor-specific effector cells through adoptive transfers. NK cells and CD8(+) T cells were major effectors which induced tumor cell death and acted in conjunction with antivascular effects. Thus, tumor homing with CpG-ODN-loaded liposomes is as potent as direct injection of free CpG-ODN and has the potential to overcome some major limitations of conventional CpG-ODN monotherapy.
authors: Western Australian Institute for Medical Research, University of Western Australia Centre for Medical Research, Perth, Australia.
authors: Juliana
authors: J
authors: Hamzah
authors: Joseph G
authors: JG
authors: Altin
authors: Thomas
authors: T
authors: Herringson
authors: Christopher R
authors: CR
authors: Parish
authors: Günter J
authors: GJ
authors: Hämmerling
authors: Helen
authors: H
authors: O'Donoghue
authors: Ruth
authors: R
authors: Ganss
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018899:CpG Islands; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D007109:Immunity / Q000187:drug effects*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008024:Ligands; D008081:Liposomes / Q000627:therapeutic use*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D051217:Toll-Like Receptor 9; D016896:Treatment Outcome
chemical_list: D008024:Ligands; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9