National Geographic discusses mRNA vaccines with UArizona Cancer Center Deputy Director, Dr. Bauman.
Molly Cassidy was studying for the Arizona bar exam in February 2019 when she felt an excruciating pain in her ear. The pain eventually radiated down through her jaw, leading her to discover a bump under her tongue. “I had several doctors tell me it was stress-related because I was studying for the bar and I had a 10-month-old son,” recalls Cassidy, who also has a Ph.D. in education. After continuing to seek medical care, she found out that she had an aggressive form of head and neck cancer that required intensive treatment.
After doctors removed part of her tongue along with 35 lymph nodes, Cassidy went through 35 sessions of radiation concurrent with three cycles of chemotherapy. Ten days after she completed treatment, Cassidy noticed a marble-like lump on her collarbone. The cancer had returned—and with a vengeance: It had spread throughout her neck and to her lungs. “By that point, I was really out of options because the other treatments hadn’t worked,” says Cassidy, now 38, who lives in Tucson. “In the summer of 2019, I was told my cancer was very severe and to get my affairs in order. I even planned my funeral.”
When doctors removed the tumor from her collarbone, they told her that she might be eligible to join a clinical trial at the University of Arizona Cancer Center that was testing an mRNA (messenger ribonucleic acid) vaccine—similar technology to the Pfizer and Moderna COVID-19 vaccines—in combination with an immunotherapy drug to treat colorectal and head and neck cancers. Whereas the COVID-19 vaccines are preventative, mRNA vaccines for cancer are therapeutic, and Cassidy jumped at the opportunity to participate. “I was at the right place at the right time for this clinical trial,” she says.
Back when people first heard about Pfizer-BioNTech and Moderna’s COVID-19 vaccines, the mRNA technology behind them sounded like the stuff of science fiction. But while the mRNA approach seems revolutionary, long before anyone had heard of COVID-19, researchers had been developing mRNA vaccines to fight cancer, autoimmune diseases such as multiple sclerosis, and to protect against other infectious diseases, such as the respiratory syncytial virus. “It’s not a new idea: What COVID has shown us is that mRNA vaccines can be an efficacious and safe technology for millions of people,” says Daniel Anderson, a leader in the field of nanotherapeutics and biomaterials at the Massachusetts Institute of Technology and a member of the Koch Institute for Integrative Cancer Research.
Currently, phase one and phase two clinical trials are recruiting participants or are underway to assess the efficacy, tolerability, and safety of therapeutic mRNA vaccines to treat various forms of cancer. These include melanoma, non-small cell lung cancers, gastrointestinal cancer, breast cancer, ovarian cancer, and pancreatic cancer, among others.
“One of the beauties of this technology is it can be used in people agnostic to their cancer type—it doesn’t matter if it’s a breast cancer or lung cancer as long as you can identify its mutations,” says Van Morris, a physician and an assistant professor of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center in Houston who is leading a phase two clinical trial exploring the use of personalized mRNA vaccines for patients who have stage II or stage III colorectal cancer. “One of the exciting things is the adaptability of the technology based on a given cancer and the underlying biology of that cancer.”
Over the course of 27 weeks, Cassidy received nine injections of a personalized mRNA vaccine along with intravenous infusions of an immunotherapy drug called Pembrolizumab. She saw her doctor, Julie E. Bauman, deputy director of the University of Arizona Cancer Center, on a weekly basis at first then every three weeks; she also had regular CT scans. After each injection, Cassidy would spike a fever and feel wiped out—with fatigue and body aches and pains—for 24 hours. “My immune system was really flaring up, which is what we wanted to happen so it could fight the cancer,” she explains.
By the time the treatment concluded in October 2020, Cassidy’s CT scans were clean: There was no evidence of cancer in her body.
A message in a needle
On a basic level, “what we’re trying to do with the mRNA vaccine for cancer is alert the immune system to the tumor so the immune system will attack it—it’s basically biological software,” explains John Cooke, a physician and medical director of the Center for RNA Therapeutics at Houston Methodist. “Vaccines are being developed against cancers where there’s not a very good solution right now or where the cancers are likely to metastasize.”
Some mRNA vaccines for cancer take an off-the-shelf approach: These ready-made vaccines are designed to look for target proteins that appear on the surface of certain cancer tumors. How well they work is a matter of speculation right now, but some experts have concerns. “The question is: What is the target? You always have to have the right thing to target for the vaccine to be effective,” says David Braun, an oncologist at the Dana-Farber Cancer Institute and Harvard Medical School who specializes in immunotherapies. After all, with cancer, there isn’t a universal target the way there is with the coronavirus’s spike protein, and DNA mutations in cancer cells vary from one patient to another.
This is where personalized mRNA cancer vaccines enter the picture—and these may be more promising, experts say. With the personalized approach, a sample of tissue is taken from a patient’s tumor and their DNA is analyzed to identify mutations that distinguish the cancer cells from the normal, healthy cells, explains Bauman, who is also chief of hematology/oncology at the UA College of Medicine-Tucson. Computers compare the two DNA samples to identify the unique mutations in a tumor, then the results are used to design a molecule of mRNA that will go into the vaccine. This is typically done in four-to-eight-weeks—“it’s a technical tour de force to be able to do that,” says Robert A. Seder, chief of the Cellular Immunology Section of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases.
After the mRNA vaccine is injected into the patient, the mRNA tells the patient’s cells to produce proteins that are associated with the specific mutations on their tumor. The tumor protein fragments that are created from the mRNA are then recognized by the patient’s immune system, Morris explains. Basically, the mRNA instructions train the immune system’s T cells—white blood cells that help us fight viruses—to recognize up to 20 mutations in cancer cells and attack only those. The immune system scours the body on a search-and-destroy mission looking for similar tumor cells.
“One of the things cancer does is it can turn on signals to tell the immune system to quiet down so the cancer is not detected,” explains Anderson. “The goal of an mRNA vaccine is to alert and gear up the immune system to go after the characteristic features of tumor cells and attack them.”
“Personalized cancer vaccines wake up specialized killer T cells that recognize abnormal cells and trigger them to kill the cells that are cancer,” Bauman says. “It’s a matter of using our own immune system as the army to eliminate the cancer.”
“This is the epitome of personalized medicine,” says Morris. “It’s a highly personalized, highly specific approach, not a one-size-fits-all treatment.”
Despite the enthusiasm and promise for this type of cancer treatment, it is important to remember: “These are early days, and the results are going to be different than the immediate success of the COVID-19 vaccines,” says Seder. For one thing, mRNA cancer vaccines aren’t going to become available at record speed the way the COVID-19 vaccines did under emergency use authorization; the cancer vaccines will require years of testing and clinical trials.
One reason for the differences in the development time for COVID-19 mRNA vaccines versus cancer mRNA vaccines stems from their therapeutic goal. The current mRNA vaccines are intended to prevent COVID-19: They’re designed to protect people from the virus by providing a preview of the coronavirus’s distinctive spike protein, so that if they encounter the virus, their immune system can fight it off. By contrast, cancer mRNA vaccines are therapies: They are given to patients to teach their immune systems to seek and destroy existing tumor cells.
Another challenge with mRNA vaccines has been to figure out how to build a nanoparticle that effectively delivers messenger RNA to where it needs to go. “If it’s [left] unprotected, messenger RNA won’t enter cells, and it will be rapidly degraded when you put it in the body,” explains Anderson. “We can protect it and deliver it inside cells by encapsulating it in a lipid-like nanoparticle.” This way, the nanoparticles can evade the body’s clearance mechanisms and get into the right cells. (Currently, lipid-based nanoparticles are the most common delivery system used in clinical trials for mRNA vaccines to treat cancer.)
Even with an optimal delivery system, however, it’s unlikely that mRNA vaccines will be a panacea for all cancers. But they are another promising tool for the treatment of advanced or incurable cancers. And researchers are exploring whether mRNA vaccines can be combined with other immune-based therapies, such as checkpoint inhibitors (which release a natural brake on the immune system so that T cells can recognize and attack tumors) or adoptive T cell therapy (in which T cells are harvested from a patient’s blood or tumor, stimulated to grow in the lab, then reinfused into a patient to help the body recognize and destroy tumor cells).
At this point, there are few published studies of trials with mRNA cancer vaccines in humans, but there are glimmers of optimism. In a phase one trial that investigated the use of an mRNA vaccine along with an immune checkpoint inhibitor in the treatment of head and neck cancer or colorectal cancer, Bauman and her colleagues found noteworthy differences: In five of the 10 patients with head and neck cancer, the combination therapy shrank the tumors and two patients had no detectable cancer after the treatment; by contrast, the 17 patients with colorectal cancer failed to respond to the combination treatment.
“With colorectal cancer, there isn’t much immune system activity—the cancer cells are better at hiding,” explains Bauman. “In some cases, it may not be enough to show the immune system what the cancer looks like.” The T cells need to reach the cancer and eliminate it. That didn’t happen with the patients who had colorectal cancer.
Hope on the horizon
Meanwhile, some promising findings are emerging from animal studies. In a study in a 2018 issue of the journal Molecular Therapy, researchers constructed an mRNA vaccine to be combined with a monoclonal antibody (a synthetic antibody made in the lab) to enhance the anti-tumor benefits in the treatment of triple negative breast cancer, which is notoriously aggressive and has a high rate of metastasis and a poor prognosis. They found that mice that were treated with the combination therapy had a significantly enhanced anti-tumor immune response compared to those who were given only the vaccine or the monoclonal antibody. And a study in a 2019 issue of the journal ACS Nano found that when mice with lymphoma (cancer of the lymphatic system) were given an mRNA vaccine along with a checkpoint inhibitor drug, they experienced significantly reduced tumor growth and 40 percent of them experienced complete tumor regression.
If mRNA vaccines prove to be effective, physicians and researchers hope that eventually vaccines could be developed to treat certain cancers, prevent recurrences, and possibly even prevent some cancers in those who are genetically predisposed to them. “I think this is going to be another arrow in the quiver for oncologists to give their patients a better chance,” says Cooke. “And if prophylactic cancer vaccines are shown to work, they could make cancer a preventable illness.”
In the meantime, Molly Cassidy is already a firm believer in the power of mRNA vaccines to treat aggressive cancers. These days, she’s feeling great and enjoying life as a stay-at-home mom with her three-year-old son, her husband, and her step-kids. “My doctor won’t say I’m cured, but she’s very happy with where I am,” says Cassidy. “This treatment saved my life, and I’m incredibly grateful to my doctors.”
Some experts say it’s conceivable that we could see an mRNA vaccine for cancer gain approval by the Food and Drug Administration within the next five years. “If we can leverage the ability of the immune system to precisely get rid of foreign invaders like cancer, that would be an amazing day,” says Bauman.