Intranasal mRNA Vaccination Provides Anti-Tumor Immunity
January 2015
In the last decade, several cancer therapies have evolved to include vaccinations as an integral part of treatment. This strategy allows the body’s own immune system to identify and attack the cancer cells while leaving healthy cells intact. Though several types of vaccines exist, recently scientists have been studying the efficacy of antigen specific mRNA. mRNA vaccines offer superior safety profiles. However the most advanced mRNA vaccination strategy involves multiple steps. Patient cells must be harvested, electroporated with antigen mRNA, matured in vitro and reinjected back into the patient. While effective, this process is laborious and costly and researchers are looking into alternative vaccination strategies.
Recently, in Scientific Reports, Phua and colleagues reported positive results for a tumor-targeted mRNA vaccine delivered intranasally. Previous work by the group demonstrated feasibility of the approach. In their first paper Phua et al. showed that Luciferase mRNA could be delivered and expressed in the nasal cavity after intranasal administration, provided it was encapsulated by a lipidoid nanoparticle. Naked mRNA was shown to degrade rapidly. A lipidoid nanoparticle (Stemfect®) with high transfection efficiency in human and mouse primary dendritic cells was specifically chosen. In vivo, a high transfection efficiency was maintained.
In their most recent paper, the group first established that the encapsulated mRNA was delivered efficiently to the Nasal-Associated Lymphoid Tissues and taken up by dendritic cells. Specifically, Phua and colleagues were able to directly visualize Cy5-labeled EGFP mRNA within CD11chigh + cells after intranasal administration. Next, to test the prophylactic capabilities of the vaccine strategy, they administered naked OVA mRNA (mOVA-N) or nanoparticle encapsulated OVA mRNA (mOVA-NP) intranasally once a week for four weeks. Seven days after the last vaccination, the authors challenged mice with EG.7 OVA cells. This is an aggressive tumor cell line and a well-characterized tumor model. They found that the mOVA-NP significantly inhibited tumor growth and increased survival efficiency as compared to the group that received either mOVA-N or a control, nanoparticle encapsulated GFP mRNA (mGFP-NP).
To test the vaccine’s therapeutic effectiveness, Phua et al. first injected mice with E.G7 OVA cells. Two days after the injection, they began the vaccine administration scheme. Each group of mice received a total of 4 immunizations over 8 days. They found that the median overall survival was significantly higher for mice that received the mOVA-NP as compared to the groups that received mGFP-NP or mOVA-N. However, while the median tumor free duration was significantly longer for mice that received the mOVA-NP as compared to those that received mGFP-NP it was not significantly different than those that received mOVA-N.
Finally, the authors looked for OVA-specific T cells. They reasoned that because T cells are the major cell type involved in tumor clearance, there should be a correlation between anti-tumor immunity and T cells presenting the OVA antigen. Consistent with this hypothesis, they observed the presence of H-2Kb OVA tetramer+ CD8+ T cells in the splenocytes isolated from mice immunized with mOVA-NP but not mOVA-N or mGFP-NP.
This study provides evidence of a mRNA vaccine that is safe, effective and economical. While naked mRNA appears to be degraded too quickly to provide an effect, other types of carriers may be compatible with this administrative route.
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