Nanoparticles transfer RNA to immune cells to activate an immune response for vaccination applications. (Image: Dr. Tara Fernandez)
RNA-based vaccines have been heralded as a new molecular weapon in the arsenal against cancer and infections. Five years ago, they were thrust into the spotlight following a $52 million investment by the Bill and Melinda Gates Foundation to CureVac, a biopharmaceutical company advancing RNA vaccines to the global health care stage.
Today, over two dozen clinical trials using personalized RNA vaccines against malignant cancers are currently underway. Nonetheless, this technology is still in its early stages.
Standing in the way of its success is a fundamental problem: the challenge of delivering RNA vaccines to particular cellular subsets with precision, while simultaneously ensuring that a robust immune response is set in motion.
Chemical engineers at MIT have turned to nanotechnology for answers, with the goal of developing an RNA vaccine against one of the deadliest cancers: melanoma. A team led by nano-drug expert Daniel Anderson together with Robert Langer, heralded as one of medicine’s most prolific inventors and entrepreneurs, recently published their work in Nature Biotechnology.
How to successfully ferry RNA into cells has, for a long time, been a head-scratcher for scientists. Naked RNA is prone to degradation by tissue nucleases. On top of that, RNA’s bulky size and negative charge hinder it from crossing the cell membrane passively. To make things worse, RNA circulating in the bloodstream can be mistaken to originate from an infectious pathogen and subsequently trigger dangerous systemic immune responses in patients.
The team at MIT had previously developed a technique that uses spherical, nano-sized capsules to shuttle the RNA molecules, protected within their cores, for various therapeutic applications. These nanoparticles are made with ionizable lipids that self-assemble with negatively-charged RNA to form tiny orbs that get engulfed and internalized by cells. Once inside the cytoplasmic space, a pH change causes nanoparticles to burst, releasing their RNA cargo into the cell’s interior.
Using the same principle for an RNA vaccine, nanoparticles would need to infiltrate an immune cell called an antigen-presenting cell (APC). These cells would then manufacture the protein encoded by the vaccine, display it on receptors on its surface, which in turn draws and activates tumour-killing lymphocytes.
Anderson and Langer’s approach was to screen over a thousand lipid formulations, each with a distinctive chemical configuration, to select those that had the best vaccine potential. A closer look revealed that nanoparticle formulations with a special structural component, a cyclic amine head group, had unique properties. These nanoparticles were not only effective transporters of RNA, but also turbo charged the immune response by activating the stimulator of interferon genes signaling pathway, or STING.
STING has proven to be an attractive target for immunotherapeutic developers, with its ability to catalyze a cascade of immune events, from flooding the body with inflammatory cytokines, to mobilizing an army of activated T-cells.
The scientists went on to test the vaccine nanoparticles in a mouse model of melanoma. For this, they used RNA targeting tyrosinase-related protein-2, or TRP-2, an enzyme that is strongly expressed by melanoma cells. Administration of the vaccines in mice significantly curbed tumour growth and prolonged their survival rate, with over 60 percent of the treated mice surviving more than 40 days.
Fascinatingly, when mice that survived were rechallenged with more tumour material, this reactivated the anti-tumour immune response — indicating the potential for prolonged protection against melanoma relapse from a single vaccination.
Melanoma is linked to genetic factors and chronic overexposure to UV radiation. Rates of melanoma diagnosis have hurtled upwards in recent decades, with survival rates estimated at just 22 percent for patients at Stage IV.
There are seven melanoma immunotherapies currently approved by the U.S. Food and Drug Administration. Unfortunately, these have had discouragingly low efficacies in patients with later stage melanomas, highlighting a desperate need for better therapeutic strategies. What’s more, a long list of infectious diseases, including HIV, ebola and malaria, are still awaiting the rise of accessible and potent vaccine safeguards.
The MIT researchers’ discovery of this RNA delivery platform and immune stimulator combo could foreseeably join the front lines of disease-fighting therapies in the near future, providing much needed hope for many.
Tara Fernandez
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