mRNA Vaccine Supercharges Immunotherapy Against Cancer

An experimental mRNA vaccine improved the tumor-fighting benefits of immunotherapy in a mouse model study, bringing researchers one step closer to their aim of generating a universal vaccination to “wake up” the immune system against cancer.

Image credit: MargJohnsonVA/Shutterstock.com

The University of Florida study, published in Nature Biomedical Engineering, found that combining the test vaccination with conventional anticancer medications known as immune checkpoint inhibitors resulted in a robust antitumor response.

One unexpected aspect, according to researchers, was that they were able to produce the encouraging outcomes by merely boosting the immune system and getting it to react as though they were combating a virus, rather than targeting a particular target protein that was produced in the tumor.

They achieved this by promoting the production of a protein known as PD-L1 within tumors, which increased the malignancies' susceptibility to therapy. The National Institutes of Health was one of several federal foundations and institutions that funded the study.

According to senior author Elias Sayour, M.D., Ph.D., a pediatric oncologist at UF Health and the Stop Children's Cancer/Bonnie R. Freeman Professor for Pediatric Oncology Research, the findings point to a possible new treatment path that could be used to treat a variety of tumor types that are resistant to chemotherapy, radiation, and surgery.

This paper describes a very unexpected and exciting observation: that even a vaccine not specific to any particular tumor or virus — so long as it is an mRNA vaccine — could lead to tumor-specific effects.

Sayour, Principal Investigator, Preston A. Wells Jr. Center for Brain Tumor Therapy, RNA Engineering Laboratory, University of Florida

“This finding is a proof of concept that these vaccines potentially could be commercialized as universal cancer vaccines to sensitize the immune system against a patient’s individual tumor,” said Sayour, who is also a McKnight Brain Institute investigator and co-leader of a program in immuno-oncology and microbiome research.

Up to now, the development of cancer vaccines has been based on two primary concepts: either identify a specific target expressed in a large number of cancer patients, or create a vaccine that targets specific targets expressed in a patient's own disease.

This study suggests a third emerging paradigm. What we found is by using a vaccine designed not to target cancer specifically but rather to stimulate a strong immunologic response, we could elicit a very strong anticancer reaction. And so this has significant potential to be broadly used across cancer patients — even possibly leading us to an off-the-shelf cancer vaccine.

Duane Mitchell, MD, PhD, Study Co-Author, University of Florida

Sayour has been in the forefront of developing high-tech anticancer vaccines for over eight years by fusing mRNA with lipid nanoparticles. Every cell, including tumor cells, has messenger RNA (mRNA), which acts as a template for the synthesis of proteins.

This new study expands on a discovery made by Sayour’s group last year: An mRNA vaccine swiftly rewired the immune system to combat glioblastoma, an aggressive brain tumor with a poor prognosis, in the first-ever human clinical study. The speed at which the novel approach, which employed a “specific” or customized vaccine created from a patient’s own tumor cells, triggered a strong immune-system reaction to reject the tumor was one of the most striking results of the four-patient experiment.

One of the most startling findings of the four-patient study was how quickly the unique technique, which used a “specific” or personalized vaccine made from a patient’s own tumor cells, elicited a robust immune-system response to reject the tumor.

When the team combined the mRNA formulation with a common immunotherapy drug known as a PD-1 inhibitor, a type of monoclonal antibody that aims to “educate” the immune system that a tumor is foreign, they observed encouraging results in mouse models of melanoma in tumors that are typically resistant to treatment, according to Sayour, a professor in the UF College of Medicine’s Department of Pediatrics and the Lillian S. Wells Department of Neurosurgery.

Taking the study a step further, the researchers discovered favorable results in mice models of skin, bone, and brain tumors when they tested a different mRNA formulation as a standalone treatment. In several models, the tumors were completely eradicated.

Sayour and colleagues observed that employing an mRNA vaccine to activate immune responses that appear unrelated to cancer might cause T cells that were previously inactive to grow and destroy the cancer if the reaction induced by the vaccination is powerful enough.

Mitchell, director of the UF Clinical and Translational Science Institute and co-director of UF's Preston A. Wells Jr. Center for Brain Tumor Therapy, said the study's implications are stunning when taken together.

“It could potentially be a universal way of waking up a patient’s own immune response to cancer. And that would be profound if generalizable to human studies.” Mitchell added.

The findings, he said, indicate the possibility of a universal cancer vaccination that might activate the immune system and ready it to function in combination with checkpoint inhibitor drugs to combat cancer — or, in certain situations, work on its own to kill cancer.

The research team is now aiming to optimize current formulations and accelerate the transition to human clinical trials.