Can mRNA Vaccines Help Treat Cancer?

The coronavirus pandemic has thrown a spotlight on messenger RNA (mRNA)—the molecule that carries a cell’s instructions for making proteinsHundreds of millions of people worldwide have received mRNA vaccines that provide powerful protection against severe COVID-19 caused by infection with SARS-CoV-2.

As stunningly successful as the mRNA COVID-19 vaccines have been, researchers have long hoped to use mRNA vaccines for a very different purpose—to treat cancer. mRNA-based cancer treatment vaccines have been tested in small trials for nearly a decade, with some promising early results.

In fact, scientists at both Pfizer-BioNTech and Moderna drew on their experience developing mRNA cancer vaccines to create their coronavirus vaccines. Now, some investigators believe the success of the mRNA COVID-19 vaccines could help accelerate clinical research on mRNA vaccines to treat cancer.

“There’s a lot of enthusiasm around mRNA right now,” said Patrick Ott, M.D., Ph.D., who directs the Center for Personal Cancer Vaccines at the Dana-Farber Cancer Institute. “The funding and resources that are flowing into mRNA vaccine research will help the cancer vaccine field.”

Dozens of clinical trials are testing mRNA treatment vaccines in people with various types of cancer, including pancreatic cancer, colorectal cancer, and melanoma. Some vaccines are being evaluated in combination with drugs that enhance the body’s immune response to tumors.

But no mRNA cancer vaccine has been approved by the US Food and Drug Administration for use either alone or with other cancer treatments.

“mRNA vaccine technology is extremely promising for infectious diseases and may lead to new kinds of vaccines,” said Elad Sharon, M.D., M.P.H., of NCI’s Division of Cancer Treatment and Diagnosis. “For other applications, such as the treatment of cancer, research on mRNA vaccines also appears promising, but these approaches have not yet proven themselves.”

With findings starting to emerge from ongoing clinical trials of mRNA cancer vaccines, researchers could soon learn more about the safety and effectiveness of these treatments, Dr. Sharon added.

How do mRNA vaccines work?

Over the past 30 years, researchers have learned how to engineer stable forms of mRNA and deliver these molecules to the body through vaccines. Once in the body, the mRNA instructs cells that take up the vaccine to produce proteins that may stimulate an immune response against these same proteins when they are present in intact viruses or tumor cells.

Among the cells likely to take up mRNA from a vaccine are dendritic cells, which are the sentinels of the immune system. After taking up and translating the mRNA, dendritic cells present the resulting proteins, or antigens, to immune cells such as T cells, starting the immune response.

“Dendritic cells act as teachers, educating T cells so that they can search for and kill cancer cells or virus-infected cells,” depending on the antigen, said Karine Breckpot, Ph.D., of the Vrije Universiteit Brussel in Belgium, who studies mRNA vaccines.

The mRNA included in the Pfizer-BioNTech and the Moderna coronavirus vaccines instructs cells to produce a version of the “spike” protein that studs the surface of SARS-CoV-2.

The immune system sees the spike protein presented by the dendritic cells as foreign and mobilizes some immune cells to produce antibodies and other immune cells to fight off the apparent infection. Having been exposed to the spike protein free of the virus, the immune system is now prepared, or primed, to react strongly to a subsequent infection with the actual SARS-CoV-2 virus.

Cancer research led to speedy development of mRNA vaccines

When the pandemic struck, mRNA vaccine technology had an unexpected opportunity to demonstrate its promise, said Norbert Pardi, Ph.D., of the University of Pennsylvania Perelman School of Medicine, whose research focuses on mRNA-based vaccines.

“The production of mRNA vaccines today is easy, fast, and can be scaled up as needed,” Dr. Pardi continued. The same manufacturing procedure can be applied to any mRNA sequence, he added.

Historically, the process of developing vaccines has taken 10 to 15 years. But both the Pfizer-BioNTech and the Moderna COVID-19 vaccines—the latter of which was developed in collaboration with NIH—were designed, manufactured, and shown to be safe and effective in people in less than a year.

“To develop an infectious disease vaccine during a pandemic, you need to be fast,” said Lena Kranz, Ph.D., co-director of Cancer Vaccines at BioNTech. “The current pandemic has confirmed our hypothesis that mRNA technology is well suited for fast vaccine development and rapid manufacturing on a global scale.”

The groundwork for the speedy design, manufacturing, and testing of the mRNA COVID-19 vaccines was established through decades of work on cancer vaccines. During this period, immunotherapy, including drugs such as immune checkpoint inhibitors, emerged as a new approach to treating cancer, leading, in some people, to dramatic and long-lasting responses.

“There’s a lot of synergy between research on immunotherapy and mRNA cancer vaccines,” said Robert Meehan, M.D., senior director of clinical development at Moderna. “Vaccines are building on the success of immune checkpoint inhibitors and expanding our knowledge of the underlying biology.”

Modifying and protecting the cargo of mRNA vaccines

Technologies that can deliver mRNA to the body are essential for the success of these vaccines. If an mRNA sequence were injected into the body without some form of protection, the sequence would be recognized by the immune system as a foreign substance and destroyed.

A solution employed by some investigational cancer vaccines is to encase the mRNA in lipid nanoparticles, which are tiny spheres that protect the mRNA molecules. Other delivery vehicles include liposomes, which are also a type of vesicle, or bubble.

“The most advanced mRNA-based vaccine platform uses mRNA encapsulated in lipid nanoparticles,” said Dr. Pardi. Now that the Pfizer-BioNTech and the Moderna coronavirus vaccine trials have demonstrated the effectiveness of lipid nanoparticles, the technology could certainly be used in future cancer vaccine trials, he added.

Another key feature of the Pfizer-BioNTech and the Moderna coronavirus vaccines is the use of modified forms of mRNA, according to Jordan Meier, Ph.D., of NCI’s Center for Cancer Research, who studies mRNA modifications.

The mRNA in these vaccines incorporates pseudouridine, which is a modification of a naturally occurring nucleoside. Nucleosides are the building blocks of mRNA, and the order of specific nucleosides determines the instructions that mRNA gives to the protein-making machinery in cells.

“The [pseudouridine] modification seems to make the mRNA itself almost invisible to the immune system,” said Dr. Meier. The modification does not alter the function of the mRNA but may enhance the effectiveness of the vaccines, he added.

Cancer researchers have been testing both modified and unmodified forms of mRNA in their investigational treatment vaccines. More research is needed to better understand the relative advantages of each approach for the development of cancer vaccines, Dr. Meier said.

Developing and testing personalized mRNA cancer vaccines

For more than a decade, cancer researchers have been developing a type of treatment known as a personalized cancer vaccine using various technologies, including mRNA and protein fragments, or peptides.

The investigational mRNA vaccines are manufactured for individuals based on the specific molecular features of their tumors. It takes 1 to 2 months to produce a personalized mRNA cancer vaccine after tissue samples have been collected from a patient.

“Speed is especially important for individualized cancer vaccination,” said Mathias Vormehr, Ph.D., codirector of Cancer Vaccines at BioNTech. “A highly individualized vaccine combination must be designed and produced within weeks of taking a tumor biopsy.”

With this approach, researchers try to elicit an immune response against abnormal proteins, or neoantigens, produced by cancer cells. Because these proteins are not found on normal cells, they are promising targets for vaccine-induced immune responses.

“Personalized cancer vaccines may teach the immune system how cancer cells are different from the rest of the body,” said Julie Bauman, M.D., deputy director of the University of Arizona Cancer Center.

Dr. Bauman is co-leading a clinical trial testing a personalized mRNA vaccine in combination with an immune checkpoint inhibitor in patients with advanced head and neck cancer. The study initially included patients with colorectal cancer, but this group did not appear to benefit from the therapy.

For patients with head and neck cancer, however, the early results were positive. Among the first 10 participants, 2 patients had all signs of their tumors disappear following treatment, known as a complete response, and another 5 had their tumors shrink.

“We were surprised to see two complete and enduring responses in our first group of patients with head and neck cancers,” said Dr. Bauman, noting that the study has been expanded to include 40 patients with the disease.

“The number of patients treated is small, but we are cautiously optimistic,” she added. The study is sponsored by Moderna, which makes each personalized vaccine in about 6 weeks.

The manufacturing process starts with the identification of genetic mutations in a patient’s tumor cells that could give rise to neoantigens. Computer algorithms then predict which neoantigens are most likely to bind to receptors on T cells and stimulate an immune response. The vaccine can include genetic sequences for up to 34 different neoantigens.

The promise of personalized immunotherapy with mRNA vaccines is “being able to activate T cells that will specifically recognize individual cancer cells based on their abnormal molecular features,” said Dr. Bauman.

Advancing the science of mRNA cancer vaccines

“A lot of immunotherapies stimulate the immune response in a nonspecific way—that is, not directly against the cancer,” said Dr. Ott. “Personalized cancer vaccines can direct the immune response to exactly where it needs to be.”

Some companies are also investigating mRNA cancer vaccines that are based on collections of a few dozen neoantigens that have been linked with certain types of cancer, including prostate cancer, gastrointestinal cancers, and melanoma.

In addition to clinical trials, fundamental research on mRNA cancer vaccines continues. Some investigators are trying to enhance the responses of immune cells to neoantigens in mRNA vaccines. One study, for example, aims to improve the responses of T cells that become exhausted while attacking tumors.

A challenge for the field is learning how best to identify neoantigens for personalized mRNA cancer vaccines, several researchers said.

“There’s still a lot we need to learn and many questions to answer,” Dr. Ott said. It’s not yet clear, for example, how personalized cancer vaccines should be best combined with other treatments, such as immune checkpoint inhibitors, he added.

As cancer researchers pursue these questions, other investigators will be developing knowledge from the growing number of people around the world who are receiving mRNA coronavirus vaccines.

Insights about the composition of mRNA or the way mRNA is packaged that emerge from studies of viruses could potentially inform work on cancer vaccines, said Dr. Breckpot.

“Unfortunately, it took a pandemic for there to be broad acceptance of mRNA vaccines among the scientific community,” she added. “But the global use of COVID-19 mRNA vaccines has demonstrated the safety of this approach and will open doors for cancer vaccines.”

‘Can mRNA Vaccines Help Treat Cancer?’ was originally published by the National Cancer Institute, , by NCI Staff

Advancing Cancer Prevention: A Conversation with NCI’s Dr. Philip Castle

July 20, 2021, by NCI Staff

Cancer Prevention word cloud

Philip Castle, Ph.D., M.P.H., joined NCI in July 2020 as director of the Division of Cancer Prevention (DCP). Dr. Castle previously worked at NCI in the Division of Cancer Epidemiology and Genetics (2002–2010), where he led numerous research projects, including studies of HPV and its connection to cervical and anal cancers. To mark his first year as DCP director, Dr. Castle discusses DCP’s priority areas and his vision for making more rapid progress in cancer prevention.

What do you see as the most promising possibilities for, and barriers to, real progress in cancer prevention over the next decade?

There are a variety of areas of promise. One area that we’re working very hard to develop is precision cancer prevention. What I mean by that is using what we know about a person—their genetics, risk factors, lifestyle—to tailor our prevention strategies. And as an anchor to that, we’re using molecular sciences to flesh out the best approaches for advancing this work.

At the same time, we want to democratize cancer prevention, developing new strategies that make proven prevention measures more broadly accessible, particularly for underserved populations. For instance, efforts to expand the use of self-sampling with HPV DNA testing for cervical cancer screening.

As for barriers to progress, I see two major issues. One that has been called the “prevention paradox”: If we’re successful with prevention, there’s nothing to observe because we’ve avoided a bad outcome—cancer. It’s what I call an “event bias,” where we tend to notice the events that occur rather than the absence of events. That’s a real hurdle, particularly for getting people to recognize the importance of prevention and support for prevention research. There is no prevention equivalent to a cancer champion.

A second barrier is the benefits-to-harms ratio of any prevention-focused interventions. When you’re talking about cancer prevention, you’re primarily dealing with generally healthy people. So the tolerance for any side effects from a prevention intervention is very low. Many people won’t get cancer in their lifetime, and you don’t want to harm anybody who was never going to get cancer. That’s the struggle we’re up against.

Prevention is a broad topic. Have you identified priority areas for the division?

Yes, there are three research arcs we’re focused on.

One is developing preventive agents. That involves identifying “druggable” targets for preventive drugs and developing the drugs themselves. That work is anchored in molecular sciences, understanding cancer-promoting signaling pathways in cells and how to interrupt them, and using that information to develop new pharmacologic agents or repurpose existing drugs for use in cancer prevention.

The second research arc is discovering biomarkers that can identify who is at increased risk of cancer. Eventually, those two areas will come together: We will be able to use a biomarker that can identify who’s at risk, and then provide a preventive agent to mitigate that risk, based on an individual’s underlying biology.

It’s about understanding who is at high risk and developing and implementing risk-informed interventions while identifying those at lower risk and backing off. It’s not one-size-fits-all prevention.

The third relates to improving symptom management in those with cancer who are undergoing treatment, which is also a part of DCP’s research portfolio. And, just like we want to do for prevention and treatment, we also want to make symptom management more precise. So we need to better understand the biology behind a person’s symptoms due to cancer and their responses to treatments.

Once we understand the biology and genetics of cancer-related and treatment-related symptoms—that is, symptom science—we can better tailor the use of current medications to prevent and/or alleviate symptoms and develop new, more effective medications in the future.

This has an important impact on survivorship: The longer we keep people with cancer healthy, the more likely they are going to be able to get the next-in-line therapy and even therapies that have not been invented today but will be tomorrow.

A big part of prevention is early detection. There’s been recent progress in the development of multicancer early detection tests. What are your thoughts about these tests?

There is clearly a tremendous amount of promise and excitement with these multicancer early detection tests, which are single tests that can potentially identify the presence of multiple cancers. And that includes cancer types for which there are currently no screening tests.

However, if we’re looking at the available evidence objectively, to date all these tests have shown is that they can detect cancer. The big question is: Can we detect the cancer at an early enough stage that we reduce the risk of death from that cancer? That’s the litmus test for any cancer screening test.

Along those lines, I fully support [NCI Director] Dr. Sharpless’s call for NCI to conduct a large clinical trial to try to answer that question.

Diet and exercise are areas of intense interest in cancer prevention. Where do you think these two areas fit into the overall prevention picture?

The thought is definitely out there that if you eat this specific thing or avoid this other thing, you’ll prevent cancer. Unfortunately, no specific foods or activities are proven to prevent cancer, except perhaps avoiding cooked red meat, and there are numerous factors that make research to identify such factors difficult to do.

Still, we know that obesity increases the risk for about 13 cancers. And we know that a healthy lifestyle, including weight management, will likely reduce your cancer risk. Of course, not everyone has equal access to healthy foods and things that promote healthy behaviors and much of that is influenced by policy matters.

But from a research perspective, one of the things we can do is find innovative ways to educate people about how to achieve a healthier lifestyle and interrupt the cycle of obesity, not just for cancer health but for their overall health.

Immunotherapy is now being studied as a potential way to help prevent cancer. Where does this research stand?

Immunotherapy has been a great advance for cancer treatment. So this “immunoprevention” research is essentially looking at whether we can harness the immune system as a form of cancer surveillance, to detect and snuff out cells with the earliest changes that will lead to cancer.

In DCP, we’re starting a new initiative to promote the discovery of preventive therapies, and that will include some immunoprevention drugs. In particular, we’re expanding activities around developing preventive agents for those at high risk for cancer, such as those with a genetic predisposition like Lynch syndrome. The idea is to start this work with a focus on the highest-risk groups, make progress for them, and then apply what we learned and work towards immunoprevention in people who are at average risk.

Some drugs have been approved for cancer prevention or risk reduction, such as tamoxifen for breast cancer, but few people have chosen to use them. Are you concerned that could happen with any new prevention drugs?

It’s an important issue. Let’s take aspirin, for example. If you’re at high risk of colorectal cancer and/or cardiovascular disease, it may make complete sense to take low-dose aspirin. However, if you walk down the street and ask somebody if they knew aspirin was a preventive agent for colorectal cancer, as hard as it might be to believe, some might say, “What is colorectal cancer?” These are real issues. And they show that a big part of our challenge is education and communication.

We know that one of the barriers of using tamoxifen as a preventive agent is its toxicity—that benefits-to-harms ratio I mentioned earlier—especially if used over long periods of time. But just as we are looking at innovative ways to deliver screening tests, there are innovative ways to deliver preventive agents so more of the drug gets to the tissue we are trying to protect and less to the other places in the body where the toxicity may occur.

In the case of tamoxifen, for example, we are funding an early-phase clinical trial on topical tamoxifen delivered to the breasts of women at high risk of breast cancer and the results to date are very promising.

Do physicians have a major role there, in educating and communicating about cancer risk and prevention?

Absolutely. We know most people feel that their doctors are the most trusted sources of medical information. But we also know that many physicians are already overwhelmed with what’s on their shoulders. They can’t spend an hour in consultation with every patient. In addition, they may not be fully up to date on the latest science. We need to educate the educator.

So we’re going to have to rely on other health experts—nurse practitioners, community health workers—to convey information about the importance of activities that promote good health, including reducing cancer risk. That means that we need to educate them as well.

What role do you see technology playing in advancing progress in prevention?

Of course it plays a very important role. As a consequence, [in DCP], we’re going to be looking for a chief technical officer to guide us in the use of new technologies for prevention.

One area where technology can have an important role is making screening tests better and faster, with point-of-care testing that can provide the results in the same day as the patent’s clinic visit. That can help reduce the number of people we lose to follow up, which is still too many.

In fact, we’re working with NCI’s SBIR program to promote the development of rapid HPV tests and at-home [hepatitis C virus (HCV)] testing. In the latter case, for example, chronic HCV infection can lead to liver cancer, but most HCV carriers don’t know that they’re carriers.

We now have very good antiviral treatments for HCV, but you can’t do anything about an infection you don’t know about. So a rapid at-home test could be an important prevention tool. As we have learned again and again, now from the COVID-19 pandemic, access is a key determinant to who participates in preventive services.

What do you see as the most important messages when it comes to cancer prevention?

I think it’s coming back to first principles. There’s that old saying: “An ounce of prevention is worth a pound of cure.” Imagine what a pound of prevention would be worth! However, that won’t happen without a philosophical shift in what we emphasize as the first line against cancer. Nobody, and I mean nobody, wants to get cancer.

And it’s important to say that we’re not going to prevent all cancers. That’s not going to be possible. But we need to take advantage of [the preventive measures] we have now. In addition, we need to press forward in a very concerted way so that we better understand the cancer process, and learn to identify who is at most risk and neutralize that risk before they develop cancer through innovative cancer prevention research.

I believe that we are entering the golden age of cancer prevention and I will do everything I can to help usher it in.

“Advancing Cancer Prevention: A Conversation with NCI’s Dr. Philip Castle was originally published by the National Cancer Institute.”

Preventing Cervical Cancer: The Development of HPV Vaccines

Key Points

  • More than half a million women around the world are diagnosed with cervical cancer each year. Over half of them will die of the disease. Most of these cases and deaths occur in low- and middle-income countries.
  • Researchers supported by the National Cancer Institute (NCI) helped establish that human papilloma virus (HPV) is a major cause of cervical cancer, carried out studies to determine how HPV causes cancer, and developed the technology used to create the first HPV vaccines.
  • Research is under way to develop the next generation of vaccines, including one that could prevent 90 percent of cervical cancers worldwide.

Pathway to Discovery

As far back as the nineteenth century, the prevailing thinking was that a sexually transmitted agent causes cervical cancer. It took more than 100 years to identify the culprit. In the 1980s, researchers at the German Cancer Research Center found types of HPV in many cervical tumors. HPV’s role in cervical cancer seemed possible, as other viruses in the HPV family were already known to cause warts. Consequently, scientists—including many supported by NCI and in the NCI Intramural program—began to explore whether HPV could cause cancer; and if it did, scientists wanted to understand how the virus could cause cancer.

NCI achieves a key milestone. A team of NCI researchers led by Joe DiPaolo, M.D., and Jay Donniger, Ph.D., was among the first to show that DNA from HPV 16, the type of HPV found most often in cervical cancer cells, was able to cause cancer-like traits in cells grown in the lab. These researchers also showed that HPV 16 and mutations (cellular transformation) caused tumors to develop. This finding suggested that several mutations or alterations needed to take place in the cell at the same time to lead to cancer.

Nearly all cervical cancers are caused by HPV. In the early 1990s, two large epidemiological studies were conducted: one by NCI intramural researcher Mark Schiffman, M.D., and another by a group at the NCI-designated Albert Einstein Cancer Center. Using what was then a new DNA technology, these studies showed that a select group of HPV types is responsible for premalignant abnormalities found in Pap smear screening and for the development of most cervical cancers. Later studies showed that nearly all cervical cancers are caused by HPV.

NCI researchers Douglas Lowy, M.D., and John Schiller, Ph.D., pioneered discoveries that led to the development of the HPV vaccine. Credit: R. Baer

Is an HPV vaccine possible? Douglas Lowy, M.D., and John Schiller, Ph.D., in the NCI intramural research program, studied how HPV genes and proteins work. As the link between HPV and cervical cancer became stronger, these researchers and other scientists explored the possibility of developing a vaccine to prevent HPV infection.

One big hurdle was that HPV produces a local genital infection and all prior attempts to develop vaccines for this type of infection had failed. In addition, a vaccine needs to be very safe, and HPV contains genes (oncogenes) that can cause cancer to develop. Scientists also did not know how to produce large quantities of the outer shell of the virus in a way that would produce antibodies that may protect against other types of infection. Consequently, researchers turned to creating something that looked like HPV but did not include the potentially dangerous genes contained within HPV.

With NCI’s support, the impossible is made possible. In the early 1990s, two research groups—including one led by Drs. Lowy and Schiller, and another laboratory supported by NCI grants—independently discovered that the proteins that form the outer shell of HPV could form particles that closely resemble the original virus and create high levels of potentially protective antibodies but are not infectious because they lack the viral genes. These virus-like particles became the basis of several subsequent HPV vaccines, including Gardasil®Cervarix®, and Gardasil® 9. All three vaccines are approved for the prevention of cervical cancer and other conditions caused by certain types of HPV.

When we started this work, there was no greater optimism for an HPV vaccine than there was for an HIV vaccine. In fact, there was skepticism that it could work at all.

Enhancing Cancer Prevention

Phase III clinical trials in young women found that Gardasil and Cervarix can prevent infection with HPV types targeted by the vaccine and prevent the development of precancerous lesions. The initial Gardasil study was so successful it was stopped early so that participants in the placebo group could also be offered the vaccine. The HPV Vaccine Trial in Costa Rica, a collaboration between investigators in Costa Rica and at NCI, demonstrated that two, and even a single, dose of Cervarix may provide a similar level of protection as the recommended three doses of the vaccine.

NCI is conducting a long-term follow-up study of women who participated in the Costa Rica trial to answer many more questions about vaccination with Cervarix, such as the extent and duration of protection.

Currently, more than 500,000 women around the world are diagnosed with cervical cancer each year and 275,000 will die of the disease. The vast majority of these cases and deaths occur in low- and middle-income countries. It has been estimated that widespread vaccination using currently available HPV vaccines could prevent more than two-thirds of cervical cancers.

Turning Discovery into Health

NCI-supported research helped establish HPV as a major cause of cervical cancer.

Although current HPV vaccines have an excellent safety record, getting people vaccinated has lagged in the United States. Research on strategies to disseminate the vaccine could help address this problem, as could efforts to enhance access to the vaccine in both developed and developing countries. Increasing awareness that the vaccine can prevent other cancers as well as cervical cancer may also help. Other research is looking at ways to simplify how the vaccines are administered to increase acceptance by the general population.

The ability of Gardasil to prevent genital warts, anal dysplasia, and anal cancer in males led to its approval by the FDA for men as well as women.  Further studies showed that two doses of the HPV vaccine can be as effective as three. The FDA, consequently, approved a two-dose regimen of Gardasil 9 for boys and girls ages 9 to 14 years old. The two-dose regimen could be very important for implementing vaccinations both in the United States and globally.

Research to Practice: NCI’s Role

NCI-supported researchers helped establish HPV as a major cause of cervical cancer, carried out studies to determine how HPV causes cancer, and developed the technology used to create the first HPV vaccines. NCI scientists also were involved in the initial trials of Cervarix and are contributing to ongoing clinical studies of the vaccine.