Immune modulatory nanoparticle therapeutics for intracerebral glioma

Neuro Oncol. 2017 Mar 1;19(3):372-382. doi: 10.1093/neuonc/now198.

Abstract

Background: Previously we showed therapeutic efficacy of unprotected miR-124 in preclinical murine models of glioblastoma, including in heterogeneous genetically engineered murine models by exploiting the immune system and thereby negating the need for direct tumor delivery. Although these data were promising, to implement clinical trials, we required a scalable formulation that afforded protection against circulatory RNases.

Methods: We devised lipid nanoparticles that encapsulate and protect the miRs from degradation and provide enhanced delivery into the immune cell compartment and tested in vivo antitumor effects.

Results: Treatment with nanoparticle-encapsulated miR-124, LUNAR-301, demonstrated a median survival exceeding 70 days, with an associated reversal of tumor-mediated immunosuppression and induction of immune memory. In both canine and murine models, the safety profile of LUNAR-301 was favorable.

Conclusions: For the first time, we show that nanoparticles can direct a therapeutic response by targeting intracellular immune pathways. Although shown in the context of gliomas, this therapeutic approach would be applicable to other malignancies.

Keywords: glioma; immunotherapy; microRNAs; nanoparticles; STAT3.

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / immunology
  • Brain Neoplasms / therapy*
  • Dogs
  • Glioma / genetics
  • Glioma / immunology
  • Glioma / therapy*
  • Humans
  • Immune Tolerance / genetics*
  • Immunologic Memory / genetics
  • Lipids / chemistry*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / administration & dosage
  • MicroRNAs / genetics*
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Lipids
  • MicroRNAs
  • Mirn124 microRNA, mouse