Targeted liposomal delivery of TLR9 ligands activates spontaneous antitumor immunity in an autochthonous cancer model.
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.
Hamzah
Juliana
J
Western Australian Institute for Medical Research, University of Western Australia Centre for Medical Research, Perth, Australia.
Altin
Joseph G
JG
Herringson
Thomas
T
Parish
Christopher R
CR
Hämmerling
Günter J
GJ
O'Donoghue
Helen
H
Ganss
Ruth
R
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
D008024:Ligands; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9