“Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders.”
Martina Prelog, MD, professor, University Hospital, Wurzburg, Germany
“In the first-in-human clinical trial involving four adult glioblastoma patients, an mRNA cancer vaccine developed at the University of Florida reprogrammed the immune system to attack the tumors.”
University of Florida Health Cancer Center
If there is a silver lining to the COVID-19 pandemic, it is the development of mRNA vaccines—vaccines that saved the lives of millions of people around the world. In addition, mRNA technology not only has the potential for developing vaccines to be used against many other RNA viruses, but there are also promising studies of the beneficial role of mRNA vaccines in the treatment of cancer.
On May 1, 2024, University of Florida (UF) researchers reported the encouraging results of the their study of a mRNA vaccine against glioblastoma, a highly malignant form of brain cancer. Hence, it seemed to be a good time for an update on mRNA vaccines for cancers.
How do vaccines work? The immune system is a complex network of cells, tissues, and organs that fight infections and diseases, such as cancer. One of the immune system’s salient properties is its capacity to remember a foreign material that has no business being in the body and fend it off before it gets a foothold. This foreign material can come from outside the body (invading microbes) or from within (mutated cells that are growing uncontrollably, that is cancer cells).
Vaccines work by introducing a weakened or inactivated germ into the body that imitates an infection. This triggers the immune system to respond by creating antibodies (protective proteins) that target the specific pathogen. Then the next time your body encounters that pathogen, the immune system is primed to respond, fight the pathogen, and help you resist developing disease.
Antigens—protein components of pathogens that teach the immune system what is foreign (non-self) or not (self)—are a critical component of any vaccine. Most vaccines for viral or bacterial infections use a weakened or inactivated germ as the antigen and only this specific antigen is necessary for the vaccine to be effective for millions of people.
How do mRNA vaccines work? Messenger RNA (mRNA) is a genetic material that tells your body how to make proteins. The process goes on constantly. (In the human body, there are over 100,000 different proteins providing many different functions.)
mRNA vaccines are designed to give cells directions to make a specific protein that can help the immune system prevent and treat certain diseases. They are injected into the body. To enter cells smoothly, mRNA used in vaccines travels within a protective bubble called a Lipid Nanoparticle.
How do cancer vaccines work? Cancer cells are cells in our body that grow uncontrollably due to mutations that are associated with altered proteins. Unlike viruses and bacteria, cancer is not an invasive, foreign organism that our immune systems can detect as a pathogen and attack. Instead, with cancer, our immune system has to be taught to recognize which parts of our own cells are different or mutated.
In most cancers there are usually many antigens, and these antigens are “personalized,” that is they are different in every patient. Therefore, for each patient, a cancer vaccine requires a custom combination of many antigens based on those expressed in the patient’s tumor. Fortunately, scientists can now identify most individual mutations that have occurred in cancer cells, and they have strategies that teach the immune system to recognize these mutations in the underlying cancers.
While making cancer vaccines is considerably more challenging than is the making of vaccines against pathogens, mRNA is considered ideally suitable to do this. mRNA cancer vaccines have the ability to support personalized therapies thereby increasing efficacy and minimizing side effects. Moreover, the mRNA technology is suited to make a customized vaccine rapidly. According to some experts, one theoretically can make an mRNA vaccine in as short a time as a weekend. (An overview of the state of the art of mRNA vaccines can be found in the May 2, 2024 Medscape Medical News article by Klaus Fleck, MD, “New mRNA Vaccines in Development for Cancer and Infections.”)
What about glioblastomas? Glioblastomas affect about 3 in every 100,000 people around the world each year, and the incidence is rising. It is an aggressive type of brain tumor that is difficult to treat. People suffering with this cancer have an average survival of about one year. Thus, the prospects for anyone diagnosed with this tumor are dire.
A recent report from UF researchers, however, offers hope. (See “Cancer Vaccine Tested in Glioblastoma Patients Shows Potential of mRNA Aggregates,” in May 1, 2024 Genetic Engineering and Biotechnology News). In this study, UF researchers used a mRNA vaccine to treat 10 dogs that had spontaneously developed brain tumors. (The owners enrolled the dogs in the study as there were no other treatment options for their pets.) Following a very favorable clinical response in the dogs, the scientists expanded their research to a small clinical trial in patients with glioblastomas. (The Food and Drug Administration approved this trial.)
They administered a mRNA vaccine intravenously in four adults with terminal glioblastomas. The vaccine was personalized for each patient with RNA first extracted from each of the patient’s surgically removed tumor. (Elias Seyour, MD, PhD, the UF pediatric oncologist who pioneered the new vaccine, is the senior author of the team’s May 1, 2024 report published in Cell, titled “RNA aggregates harness the danger response for cancer immunotherapy.”) The mRNA was then amplified and wrapped in newly designed packaging of lipid nanoparticles that made the tumor cells “look” like a dangerous virus when it was injected into the bloodstream.
The researchers were impressed by the vigorous immune system response to reject the tumor within 48 hours of delivering the mRNA vaccine. As Elias Seyour said, “This is significant because it takes time—weeks to months with boosters—for vaccines to begin working.” He also commented that the scientists “expect this work to create a new paradigm that rapidly activates the immune system against cancer.”
The next step for these UF researchers is to carry out an expanded Phase I clinical trial, including up to 24 patients (both children and adults). This study should not only validate the initial findings but also provide a better idea of how long the immune response will last.
Interestingly, at about that same time that the UF clinical trial results were published, a research group at UCLA Health Jonsson Comprehensive Cancer Center published the results of another immunologic (non-mRNA vaccine) approach to treating glioblastomas. (See Nature Communications, “TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial.”) The study found that “pairing the personalized dendritic cell vaccine with the immune-boosting substance poly ICLC enhances the immune response and T cells in patients with malignant glioma, and improves the dendritic cells’ ability to fight the brain tumor more effectively than the vaccine alone.” (See “Adding immune-boosting agent to personalized cancer vaccine supercharges the body’s immune defense against malignant brain tumors.”) Dr. Prins, co-author of the study, said, “By improving the potency of the vaccine, we’re hoping it can induce more effective anti-tumor immune responses in patients diagnosed with malignant gliomas.”
What are the future prospects of mRNA vaccines? After heart disease, cancer is the second most common cause of death in the U.S. And the need for better treatments of malignancies like glioblastomas is urgent. Thus, it is heartening to know that in addition to glioblastomas, mRNA vaccine trials are underway for other cancers with prognoses similar to glioblastomas, such as lung, pancreas, and skin cancer (melanoma).
In addition, when you consider the potential impact of mRNA vaccines for RNA viruses, such as HIV, influenza, as well as other coronaviruses like Middle East Respiratory Syndrome virus, the prospects for mRNA vaccines appear very bright.
According to Yuval Noah Harari, historian, philosopher and author of the highly acclaimed book Sapiens: A Brief History of Human Kind, “Questions you cannot answer are usually far better for you than answers you cannot question. “ I have no definitive answer to where the field of mRNA vaccines will take us, but I do know that this is an exhilarating time for researchers in the fields of infectious diseases and oncology, and, more importantly, a hopeful time for cancer patients.
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