Immune modulatory nanoparticle therapeutics for intracerebral glioma


Authors: Nasser K. Yaghi et al.

Journal: Neuro-Oncology

DOI: 10.1093/neuonc/now198

Publication - Summary

March 01, 2017

Summary

Small interfering RNAs (siRNA) and microRNAs (miRNA) have gained a lot of clinical interest in recent years as they can specifically target genes/ proteins of interest and can be engineered to fit the patients’ unique needs and conditions. Different methods have been developed to deliver RNA molecules in vitro and in vivo, however, the clinical application of RNA interference has been challenging due to the need for a safe, scalable and clinically relevant delivery method. Cationic lipoplex reagents for example, are marketed for in vivo delivery but at limited doses and cannot be used in humans.  In their article published in Neuro-Oncology, 2017, the Heimberger group from The University of Texas, in collaboration with Arcturus Therapeutics describe a lipid nanoparticle system (LNP) that can be used to deliver mimic miRNA to immune cells for treatment of glioma. Using a NanoAssemblrTM BlazeTM instrument, they generated large scale miRNA-LNP formulations to perform preclinical studies in a canine model. This study is the first to highlight the efficacy and scalability of nanoparticles for delivery of miRNA as an immune therapeutic for treatment of malignancy.

To develop an efficacious miRNA delivery system, the authors first generated 4 test LNP formulations with different lipid compositions encapsulating the miRNA sequence miR-124. miR-124 targets a tumor-mediated immune suppressive hub, STAT3, and has been shown to have therapeutic effects in preclinical malignancy models. Of the 4 test miR-124 LNPs, one named LUNAR-301 significantly prolonged the median survival time of the murine glioblastoma model and was chosen for further investigation. LUNAR-301 was injected to non-tumor-bearing mice for pharmacokinetic studies and was compared to its lipoplex counterpart, Lipofectamine. Analysis of the desired immune compartment, peripheral blood mononuclear cells (PBMCs), indicated higher uptake of miR-124 LUNAR-301 compared to Lipofectamine. Further analysis indicated that LUNAR-301 preferentially targeted monocytes, which are an important site of STAT3 regulation.

To assess immunity against tumor recurrence, LUNAR-301 as well as the Lipofectamine miR-124 treated glioma-implanted mice that survived the initial implantation were rechallenged with a second and third intracerebral glioma implant. No further treatment was administered to these mice and a greater number of LUNAR-301 treated mice survived the second and third challenge compared to the Lipofectamine group. This also pointed to induction of immunological memory in response to LUNAR-301 administration. Interestingly, this is contrary to the general property of anti-STAT3 agents which usually do not generate immunological memory, highlighting the superiority of LUNAR-301 to its small molecule counterparts.

Additionally, LUNAR-301 was tested for toxicity in non-tumor-bearing mice. Mice treated with LUNAR-301 maintained their body weight while the liver weight was slightly increased and it was observed that generally nonspecific immune activation was not triggered compared to the PBS control. LUNAR-301 was then formulated in large scale and tested in purpose-bred non-tumor-bearing beagles. No organ abnormalities were observed following injection and LUNAR-301 accumulated in the PBMC compartment.

Overall, LUNAR-301 is a safe and efficacious way to deliver miRNA to immune cells to treat malignancy and can build protection against tumor recurrence. In addition to long term stability, LUNAR nanoparticles can be tolerated at high doses, are biodegradable and can be upscaled for clinical studies. LUNAR nanoparticles are thus highly superior to existing lipoplex gene delivery agents such as Lipofectamine for in vivo applications. This study indicates that miRNA-lipid nanoparticles are safe and efficacious in multiple species and can target specific tissues to treat malignancy. Currently several LNP formulations are undergoing clinical trials and the authors suggest that LUNAR-301 can also potentially be used as an effective delivery method in humans.

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.

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