Immune modulatory nanoparticle therapeutics for intracerebral glioma

Nasser K. Yaghi, Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Jun Wei, Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Yuuri Hashimoto, Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Ling-Yuan Kong, Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Konrad Gabrusiewicz, Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Edjah K. Nduom, Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Xiaoyang Ling, Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Neal Huang, Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Shouhao Zhou, Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Brittany C. Kerrigan, Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Jonathan M. Levine, Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, Texas, USA.
Virginia R. Fajt, Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, Texas, USA.
Gwendolyn Levine, Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, Texas, USA.
Brian F. Porter, Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, Texas, USA.
Eric G. Marcusson, Arcturus Therapeutics, San Diego, California, USA.
Kiyoshi Tachikawa, Arcturus Therapeutics, San Diego, California, USA.
Padmanabh Chivukula, Arcturus Therapeutics, San Diego, California, USA.
David C. Webb, Arcturus Therapeutics, San Diego, California, USA.
Joseph E. Payne, Arcturus Therapeutics, San Diego, California, USA.
Amy B. Heimberger, Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

Document Type

Article

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.

Medical Subject Headings

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

Publication Date

3-1-2017

Publication Title

Neuro-oncology

E-ISSN

1523-5866

Volume

19

Issue

3

First Page

372

Last Page

382

PubMed ID

27765835

Digital Object Identifier (DOI)

10.1093/neuonc/now198

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