Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy

Biomaterials. 2011 Aug;32(22):5134-47. doi: 10.1016/j.biomaterials.2011.03.067. Epub 2011 Apr 22.

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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / chemistry
  • Antibodies / metabolism
  • Antibodies / therapeutic use*
  • CD40 Antigens / immunology
  • Cell Line, Tumor
  • Humans
  • Immunotherapy / adverse effects*
  • Immunotherapy / methods*
  • Kaplan-Meier Estimate
  • Liposomes / chemistry*
  • Liposomes / metabolism
  • Materials Testing
  • Melanoma / drug therapy
  • Melanoma / immunology
  • Mice
  • Mice, Inbred C57BL
  • Nanoparticles / chemistry
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Neoplasms / immunology*
  • Oligodeoxyribonucleotides / chemistry
  • Oligodeoxyribonucleotides / immunology
  • Polyethylene Glycols / chemistry
  • Tissue Distribution

Substances

  • Antibodies
  • CD40 Antigens
  • CPG-oligonucleotide
  • Liposomes
  • Oligodeoxyribonucleotides
  • Polyethylene Glycols