Researchers have designed a new nanoparticle that was shown to more effectively deliver a cancer-fighting mRNA vaccine to mice. The study’s results may lead to the development of better vaccines to treat cancer and infectious diseases like COVID-19.
Cancer treatment has been revolutionalized by advances made, and continuing to be made, in the field of immunotherapy, the treatment of disease by activating or suppressing the body’s immune system. But each patient’s cancer tumor is unique, requiring treatments that target individual tumor-specific mutations. Using messenger RNA (mRNA) vaccines to deliver this treatment is a promising strategy.
Vaccines help prevent infection by preparing the body to fight pathogens such as bacteria or viruses. Most traditional vaccines contain a weakened or dead version of the bacteria or viruses to trigger an immune response. However, mRNA vaccines, such as the COVID-19 vaccine, work by introducing a piece of mRNA that corresponds to a protein found on the outside of a virus, causing the creation of antibodies and marking the virus for destruction. Once produced, antibodies remain in the body so it can respond quickly if the immune system is exposed to the pathogen again.
Now, a new study by researchers at Johns Hopkins Medicine may have found a way to improve the delivery of mRNA vaccines to treat infectious and non-infectious diseases.
When it comes to using mRNA vaccines to treat non-infectious diseases like cancer, the challenge has been to deliver materials to large numbers of dendritic cells, a special type of immune cells that teaches the immune system, particularly T cells, to seek and destroy cancer cells.
“The immune system is designed to work through an amplified response, where dendritic cells teach other immune cells what to look for in the body,” said Jordan Green, corresponding author of the study.
Making stronger vaccines requires the nanoparticles carrying the mRNA to reach, enter and be expressed in the dendritic cells. After expression, the mRNA degrades and the resultant immune response lasts much longer.
COVID-19 mRNA vaccines comprise nanoparticles made from lipids, a type of fatty acid, that are injected into the muscle. But, there are relatively few dendritic cells in muscle. Injecting the mRNA vaccine into the bloodstream also causes delivery problems, because the vaccine tends to head straight for the liver, where it is broken down. So, researchers set their sights on an organ with a far higher number of dendritic cells: the spleen.
“Our goal was to develop a nanoparticle that wouldn’t be sent directly to the liver and could effectively teach immune system cells to seek and destroy the appropriate target,” said Green.
After testing a number of materials, the researchers decided to encase their mRNA in a polymer-based nanoparticle with just the right ratio of water-loving and water-phobic molecules to enable it to enter the target cell. The polymers contained molecules with an affinity for a specific tissue type which, here, was the spleen. In addition, a helper or adjuvant was added to the nanoparticle to activate the dendritic cells.
Testing their novel nanoparticle configuration on mice, they found that it avoided the liver and was taken up by the splenic cells at levels about fifty-fold higher than mRNA by itself would’ve been. Nearly 80% of the splenic cells that the nanoparticles reached were the target dendritic cells.
In mice with immune cells genetically engineered to glow red when the nanoparticle delivered its mRNA contents, the researchers found that 5% to 6% of all dendritic cells in the spleen successfully took up, opened, and processed the nanoparticle. This was observed more in dendritic cells than in other immune cells. The nanoparticles then biodegraded into safe byproducts.
Once it was proven that the new nanoparticle would successfully target the spleen’s dendritic cells, the researchers armed it with an immunotherapy drug and tested it on mice again. They found that half of the mice models with colorectal cancer survived long-term after receiving two injections, compared with 10% to 30% that survived after being treated with other nanoparticle formulations containing an immunotherapy drug or the immunotherapy drug alone.
When the surviving mice were given additional colorectal cancer cells, they all lived without additional treatment, suggesting to the researchers that their nanoparticle provided a long-term immune response that prevented cancer from returning. They also found that 21 days after treatment, 60% of the cell-killing T cells recognized and attacked the colorectal cancer cells.
The researchers saw a similar response in mice models with melanoma, where about half of the same type of T cells were primed to attack the melanoma cells.
“The nanoparticle delivery system was able to create an army of T cells that can recognize cancer-linked antigen,” said Green. “This new nanoparticle delivery system may improve the way vaccines are given for infectious disease, and it may open a new avenue for treating cancer as well."
The study was published in the journal PNAS.
Source: Johns Hopkins Medicine
