New mRNA vaccine trains immune cells to fight pancreatic cancer in mice

A novel mRNA vaccine effectively triggered an antitumor immune response in a mouse model of pancreatic cancer, even completely eliminating the cancer in a few mice, according to a new study.

The experimental vaccine contains two key molecular modifications that make it especially well-suited to stimulating the immune system to attack cancer cells: first, it uses what’s known as a series-connected design where multiple immune targets are combined on one mRNA molecule, and second, it is wrapped in a membrane derived from molecular shipping containers that immune cells use to communicate with each other.

These combined approaches offer “a versatile strategy for the development of mRNA cancer vaccines against [pancreatic cancers] and potentially other solid tumors,” researchers wrote in a study, “Engineered exosome-lymphotropic mRNA vaccine encoding series-connected antigens elicits potent antitumor immunity in pancreatic cancer,” published in the International Journal of Pharmaceutics.

Vaccines work by teaching the immune system to attack a specific molecular target. Cancer vaccines apply this concept by training immune cells to recognize proteins specific to tumor cells. In pancreatic cancer, the KRAS protein is almost always mutated, making it a promising focus for vaccine development.

When genes are read to make proteins, the genetic code is transcribed into a temporary molecule called mRNA (messenger RNA), which serves as the template for protein production. Whereas conventional vaccines usually use proteins to trigger an immune response, mRNA vaccines provide genetic instructions that prompt immune cells to manufacture those target proteins themselves. mRNA vaccines are promising because their genetic codes can be easily tweaked, and several candidates designed to treat cancer are already in clinical trials.

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How series-connected designs target pancreatic tumors

Anticancer mRNA vaccines typically aim to trigger an immune response against multiple targets simultaneously to promote a robust antitumor immune response. Traditionally, this is done using a parallel-connected strategy — basically meaning that the vaccine contains multiple mRNA molecules, one for each target.

In this study, the researchers built their vaccine using a different approach called the series-connected design. Instead of using separate mRNA molecules for each target, they crafted a single mRNA molecule encoding all targets at once. Their vaccine specifically encodes five targets derived from the mutant KRAS protein.

The team tested their vaccine in a mouse model where pancreatic cancer cells were injected beneath the skin and allowed to grow into tumors. They evaluated their series-connected vaccine against a traditional parallel-connected vaccine, both designed to target the same KRAS sequences.

Results indicated that both vaccines reduced tumor growth, but the series-connected vaccine proved superior at activating cancer-killing T-cells. The series-connected vaccine also led to the complete disappearance of tumors in two mice, the researchers noted.

When creating an mRNA vaccine, determining the right sequence is only part of the challenge; delivering it effectively into immune cells poses another major hurdle. For their vaccine, the researchers encapsulated the mRNA within engineered nanoparticles coated with material from exosomes — microscopic shipping containers that cells use to exchange molecules and communicate. Specifically, they harvested exosomes from dendritic cells, an immune cell type that plays a central role in triggering immune responses.

In mouse experiments, the researchers’ series-connected vaccine with this exosome coating elicited a stronger antitumor immune response than the same vaccine using uncoated nanoparticles.

“In summary, we developed a dual-modality mRNA vaccine platform that integrates [a series-connected] KRAS mRNA design with an exosome-engineered lipid nanoparticle,” the researchers concluded. The series-connected strategy “elicited stronger KRAS-specific cellular immunity and superior antitumor efficacy” than the conventional parallel-connected design, while the exosome-coated nanoparticles enhanced immune cell activation without overt toxicity.