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Targeted Liposomal Delivery of TLR9 Ligands Activates Spontaneous Antitumor Immunity in an Autochthonous Cancer Model¹

Juliana Hamzah^*, Joseph G. Altin, Thomas Herringson, Christopher R. Parish, Günter J. Hämmerling, Helen O'Donoghue^* and Ruth Ganss^2,*

*Western Australian Institute for Medical Research, University of Western Australia Centre for Medical Research, Perth, Australia; Biochemistry and Molecular Biology, School of Biology and Division of Immunology and Genetics, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, Australian National University, Canberra; and Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany

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.

²Address correspondence and reprint requests to Dr. Ruth Ganss, Western Australian Institute for Medical Research, Rear, 50 Murray Street, Medical Research Foundation Building, Level 5, Perth, WA 6000, Australia.E-mail address: ganss{at}waimr.uwa.edu.au

¹ This work was supported by grants from the Medical Research Foundation, Royal Perth Hospital, the National Health and Medical Research Council (Project Grants 572578 to R.G. and 316949 to J.G.A.), the Cancer Council Western Australia (toJ.H.), and start-up funds from the Western Australian Institute for Medical Research and the University of Western Australia (to R.G.).