Surprising finding could pave way for universal cancer vaccine

An experimental mRNA vaccine boosted the tumor-fighting effects of immunotherapy in a mouse-model study, bringing researchers one step closer to their goal of developing a universal vaccine to “wake up” the immune system against cancer.

Published today in Nature Biomedical Engineering, the University of Florida study showed that like a one-two punch, pairing the test vaccine with common anticancer drugs called immune checkpoint inhibitors triggered a strong antitumor response.

A surprising element, researchers said, was that they achieved the promising results not by attacking a specific target protein expressed in the tumor, but by simply revving up the immune system — spurring it to respond as if fighting a virus. They did this by stimulating the expression of a protein called PD-L1 inside of tumors, making them more receptive to treatment. The research was supported by multiple federal agencies and foundations, including the National Institutes of Health.

Senior author Elias Sayour, M.D., Ph.D., a UF Health pediatric oncologist, said the results reveal a potential new treatment path — an alternative to surgery, radiation and chemotherapy — with broad implications for battling many types of treatment-resistant tumors.

“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,” said Sayour, principal investigator at the RNA Engineering Laboratory within UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy.

“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, a McKnight Brain Institute investigator and co-leader of a program in immuno-oncology and microbiome research.

Until now, there have been two main ideas in cancer-vaccine development: To find a specific target expressed in many people with cancer, or to tailor a vaccine that is specific to targets expressed within a patient's own cancer.

“This study suggests a third emerging paradigm,” said Duane Mitchell, M.D., Ph.D., a co-author of the paper. “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.”

For more than eight years, Sayour has pioneered high-tech anticancer vaccines by combining lipid nanoparticles and mRNA. Short for messenger RNA, mRNA is found inside every cell — including tumor cells — and serves as a blueprint for protein production.

This new study builds upon a breakthrough last year by Sayour’s lab: In a first-ever human clinical trial, an mRNA vaccine quickly reprogrammed the immune system to attack glioblastoma, an aggressive brain tumor with a dismal prognosis. Among the most impressive findings in the four-patient trial was how quickly the new method — which used a “specific” or personalized vaccine made using a patient’s own tumor cells — spurred a vigorous immune-system response to reject the tumor.

In the latest study, Sayour’s research team adapted their technology to test a “generalized” mRNA vaccine — meaning it was not aimed at a specific virus or mutated cells of cancer but engineered simply to prompt a strong immune system response. The mRNA formulation was made similarly to the COVID-19 vaccines, rooted in similar technology, but wasn’t aimed directly at the well-known spike protein of COVID.

In mouse models of melanoma, the team saw promising results in normally treatment-resistant tumors when combining the mRNA formulation with a common immunotherapy drug called a PD-1 inhibitor, a type of monoclonal antibody that attempts to “educate” the immune system that a tumor is foreign, said Sayour, a professor in UF’s Lillian S. Wells Department of Neurosurgery and the Department of Pediatrics in the UF College of Medicine.

Taking the research a step further, in mouse models of skin, bone and brain cancers, the investigators found beneficial effects when testing a different mRNA formulation as a solo treatment. In some models, the tumors were eliminated entirely.

Sayour and colleagues observed that using an mRNA vaccine to activate immune responses seemingly unrelated to cancer could prompt T cells that weren’t working before to actually multiply and kill the cancer if the response spurred by the vaccine is strong enough.

Taken together, the study’s implications are striking, said Mitchell, who directs the UF Clinical and Translational Science Institute and co-directs UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy.

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

The results, he said, show potential for a universal cancer vaccine that could activate the immune system and prime it to work in tandem with checkpoint inhibitor drugs to seize upon cancer — or in some cases, even work on its own to kill cancer.

Now, the research team is working to improve current formulations and move to human clinical trials as rapidly as possible.