title: Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy.
abstract: Immunostimulatory therapies that activate immune response pathways are of great interest for overcoming the immunosuppression present in advanced tumors. Agonistic anti-CD40 antibodies and CpG oligonucleotides have previously demonstrated potent, synergistic anti-tumor effects, but their clinical use even as monotherapies is hampered by dose-limiting inflammatory toxicity provoked upon systemic exposure. We hypothesized that by anchoring immuno-agonist compounds to lipid nanoparticles we could retain the bioactivity of therapeutics in the local tumor tissue and tumor-draining lymph node, but limit systemic exposure to these potent molecules. We prepared PEGylated liposomes bearing surface-conjugated anti-CD40 and CpG and assessed their therapeutic efficacy and systemic toxicity compared to soluble versions of the same immuno-agonists, injected intratumorally in the B16F10 murine model of melanoma. Anti-CD40/CpG-liposomes significantly inhibited tumor growth and induced a survival benefit similar to locally injected soluble anti-CD40 + CpG. Biodistribution analyses following local delivery showed that the liposomal carriers successfully sequestered anti-CD40 and CpG in vivo, reducing leakage into systemic circulation while allowing draining to the tumor-proximal lymph node. Contrary to locally-administered soluble immunotherapy, anti-CD40/CpG-liposomes did not elicit significant increases in serum levels of ALT enzyme, systemic inflammatory cytokines, or overall weight loss, confirming that off-target inflammatory effects had been minimized. The development of a delivery strategy capable of inducing robust anti-tumor responses concurrent with minimal systemic side effects is crucial for the continued progress of potent immunotherapies toward widespread clinical translation.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, 77 Mass. Ave., Cambridge, MA 02139, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Kwong
authors.forename: Haipeng
authors.initials: H
authors.lastname: Liu
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects* / Q000379:methods*; D053208:Kaplan-Meier Estimate; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D008422:Materials Testing; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000276:immunology; D011092:Polyethylene Glycols / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D000906:Antibodies; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D011092:Polyethylene Glycols