Cancer puts up a formidable defense. As cancer cells grow, they pump out molecules that weaken and confuse attacking immune cells, lowering their ability to fight off tumors.
A team from the University of Florida have now found a way to “wake up” the immune system, such that immune cells regain their cancer-fighting abilities. An injection made with the mRNA technology used in Covid vaccines—with some small tweaks—paired up with a commonly used cancer immunotherapy medication to destroy skin, bone, and brain tumors in mice.
The treatment differs from previous anti-cancer drugs. Rather than directly targeting cancer cells, mRNA vaccines generate proteins that signal the presence of cancers and rev up the immune system. Because they’re not specific to any one type of cancer, the strategy could bolster immunotherapy treatment of multiple cancers.
The “very unexpected and exciting” 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 Elias Sayour, who led the study, in a press release.
Molecular Fog
As cancers grow, they evade their natural predator—the immune system.
Most cancers have proteins that immune T cells recognize as foreign, marking them as targets for destruction. Other parts of the immune system also take action, pumping out bullet-like molecules called cytokines that destroy cancerous cells.
But tumor cells can counter the attack. With time, they build a fortress—called the tumor microenvironment—packed with molecules that reduce immune-cell efficacy. This molecular fog prevents the body’s defenses from recognizing the dangerous cells and lets them grow. Some molecules also actively shut down surveilling T cells, kneecapping the immune response.
One way to overcome this is to boost the immune system with immunotherapy. These drugs, called immune checkpoint inhibitors, artificially ramp up immunity to destroy cancer cells. While they have “revolutionized cancer therapy,” they still rely on T cells to recognize cancer—which remains a struggle because of the protective barrier, wrote the team.
Another strategy is to find and break down the molecular signaling making up the barrier.
Decades of research have homed in on proteins called interferons. These messengers usually alert the immune system after a viral infection or when they find cancer. Increasing their activity seems reasonable as an anti-cancer treatment. But interferons are double agents. Some mask developing tumors from immune cells’ watchful eyes, and overproduction triggers chronic inflammation that also increases cancer resilience to immunotherapies.
Trojan Horse
The new study waded into these muddy immune waters to parse the effect of interferons in cancer development. The proteins trigger multiple downstream signals that can rapidly alter tumor growth and the tumor barrier against immune attacks.
After analyzing cancer growth and spread in mice with multiple types of tumors—skin, bone, and brain—the team found an early window in which increased interferon activity led to worse health outcomes.
Most of the proteins regulating interferons were in tumors, making them a perfect target for immune cells. Increasing the levels of these proteins could “wake up” the immune system and get attacking cells to penetrate the cancer barrier.
Enter mRNA vaccines. Beyond Covid, mRNA vaccines in the works are tackling a wide range of diseases. The vaccines incorporate bits of unique genetic code into a shot. When injected, the body uses the code to make proteins. And these train the immune system to recognize a threat. For Covid-19, mRNA vaccines encoded a spike protein dotted on the surface of the virus. Once the immune system learns the intruder’s signature, it can better tackle the real virus if infected.
The same strategy works for cancer cells: mRNA vaccines containing cancer protein “signatures” can train the immune system to attack those cancers. Scientists have already sequenced a patient’s cancer protein fingerprint and generated personalized mRNA vaccines that mimic their cancer, in turn teaching their bodies to fight back against the actual tumors.
A year ago, Sayour’s team engineered mRNA vaccines to tweak immune responses in four people with glioblastoma, a highly aggressive brain cancer. The vaccines were tailored to the patients, in that they encoded the protein signatures for each specific tumor. The team also designed a different fatty “wrapper”—looking more like an onion rather than the bubble used in Covid vaccines—to protect the mRNA payload and increase its affinity to cancer cells.
Though promising, personalization takes time and is expensive and hard to scale up.
The new study went broader. The team engineered several mRNA molecules to stimulate the interferon response, a process that works similarly in multiple types of cancers. Like shining a light through dense fog, the vaccine guided immune cells past a cancer’s molecular barrier in mice. Without tailoring the recipe to specific cancers—skin, lung, bone, or brain—the vaccine, given weekly with an approved immunotherapy drug, reduced tumor size and growth within days.
In the case of lung cancer, most mice died within 40 days without a vaccine. But for those given the treatment, roughly 40 percent survived at least 100 days. The same mRNA vaccine also increased survival from 80 to over 200 days in mice with an aggressive brain cancer.
Because the interferon system is integral to our immune response, tinkering with it could bring unexpected side effects. In mice and pet dogs with brain cancer—the latter assessed after full consent from their owners—the vaccine was found safe for both liver and kidney function.
Surprisingly, the cancer-targeting effect spilled over to other cancer cells with different “red flag” proteins behind the barrier. This shows the strategy can educate the immune system to go after multiple dangerous proteins. Subsequent immune attacks further eliminated nearby cancerous cells, with the immune response self-amplifying along the way.
The results are only in mice, but the team is working towards a clinical trial. If successful, mRNA vaccines could add another treatment option for stubborn cancers alongside current immunotherapy drugs.
“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,” said study author Duane Mitchell. “And so this has significant potential to be broadly used across cancer patients—even possibly leading us to an off-the-shelf cancer vaccine.”
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