Can mRNA Vaccines Help Treat Cancer?

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The coronavirus pandemic has thrown a spotlight on messenger RNA (mRNA)—the molecule that carries a cell’s instructions for making proteins. Hundreds 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

What’s New in Colorectal Cancer Research?

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Colorectal cancer awareness monthResearch is always going on in the area of colorectal cancer. Scientists are looking for causes and ways to prevent colorectal cancer, better ways to find it early (when it’s small and easier to treat), and ways to improve treatments. Here are some examples of current research. Treatment in a clinical trial is often the only way to get these treatments.

Reducing colorectal cancer risk

Many studies are looking to identify the causes of colorectal cancer. The hope is that this might lead to new ways to help prevent it.

Other studies are looking to see if certain types of diets, dietary supplements, or medicines can lower a person’s risk of colorectal cancer. For example, many studies have shown that aspirin and pain relievers like it might help lower the risk of colorectal cancer, but these drugs can have serious side effects. Researchers are now trying to figure out if the benefits might outweigh the risks for certain groups of people thought to be at high colorectal cancer risk.

Early detection

Doctors are looking for better ways to find colorectal cancer early by studying new types of screening tests (like blood tests) and improving the ones already being used. Researchers are also trying to figure out if there’s any test or screening plan that clearly works best.

They’re also looking for ways to educate and encourage people to get the routine screening tests that are available today and known to help reduce the number of deaths from this cancer.

Diagnosis

Researchers are trying to define colorectal cancer sub-types. This means grouping colorectal cancers based on things like the genetic mutations in the cancer cells, how the cells look and behave, how fast the cells are dividing, and features of the tumor itself. As has been found with other cancer types, this might lead to better understanding of disease progression and outcomes, as well as more clearly defined treatment plans (precision medicine).

Gene tests to help plan treatment

As doctors continue to learn more about the gene changes in colorectal cancer cells, certain gene tests have been developed to help predict which patients have a higher risk of colorectal cancer recurrence (the cancer coming back after treatment). These tests are being studied to see if they might help decide and if more treatment is needed after surgery and if they can predict outcomes.

Liquid biopsy to help plan treatment

Researchers are studying liquid biopsies for cancer diagnosis and treatment. A liquid biopsy is most often a sample of blood that is taken for cancer testing. It is much easier to get a sample of blood than it is to get a sample of the tumor with a needle. And studies have shown that liquid biopsies contain cancer cells as well as pieces of DNA from the cancer. Liquid biopsies might also be samples of urine, spinal fluid, or pleural effusions (fluid around the lungs).

Current research is testing colorectal cancer DNA from liquid biopsies to find specific gene mutations (changes). Researchers are hoping to find out if the gene changes could help doctors choose the best drugs for patients. Studies are also looking at if rising liquid biopsy tumor DNA levels predict that a cancer is no longer responding to certain drugs before an imaging test is done, or if it might predict the cancer is coming back after treatment (recurring).

Treatment

Researchers are always looking for better ways to treat colorectal cancer.

Surgery

Surgeons continue to improve the operations used for colorectal cancers. Rectal cancer surgery done through the anus, without cutting the skin, is also being studied.

Organ preservation — keeping your body working the way it normally does — is another research goal. For instance, doctors are looking at the ideal timing of surgery after chemo is used to shrink a rectal tumor and how to know when they’ve got the best response in each patient.

Sometimes when colorectal cancer recurs (comes back), it spreads to the peritoneum (the thin lining of the abdominal cavity and organs inside the abdomen). These cancers are often hard to treat. Surgeons have been studying a procedure called hyperthermic intraperitoneal chemotherapy (HIPEC). First, surgery is done to remove as much of the cancer in the belly as possible. Then, while still in the operating room, the abdominal cavity is bathed in heated chemotherapy drugs. This puts the chemo right in contact with the cancer cells, and the heat is thought to help the drugs work better. Some patients are living longer with this type of treatment, but more studies are needed to know which patients it can help. Doctors and nurses with special training and specialized equipment are also needed, so it’s not widely available.

For colorectal cancer that has spread to the liver and can’t be removed by surgery, another procedure being studied is hepatic arterial infusion chemotherapy (HAIC)  which often requires surgery. In this procedure, a pump or port (similar to a port for IV chemo but larger) is implanted close to the hepatic artery, which is the blood vessel feeding most cancers in the liver. The doctor can put chemo into the pump which is then released directly into the liver and helps kill the cancer cells while leaving healthy liver cells unharmed. Often, this procedure is given along with systemic chemo (chemotherapy given through a vein or CVC) to help tumors in the liver shrink more than if they had only gotten IV chemo, and hopefully make them able to be removed by surgery. More research is being done to find out which patients are the best candidates for this procedure. Currently it can only be done in facilities that are experienced.

Chemotherapy

Chemotherapy is an important part of treatment for many people with colorectal cancer, and doctors are constantly trying to make it more effective and safer. Different approaches are being tested in clinical trials, including:

  • Testing new chemo drugs or drugs that are already used against other cancers.
  • Looking for new ways to combine drugs already known to work against colorectal cancer to see if they work better together.
  • Studying the best ways to combine chemotherapy with radiation therapy, targeted therapies, and/or immunotherapy.

Better ways to identify, prevent, and treat chemo side effects are other areas of research interest.

Targeted therapy

Targeted therapy drugs work differently from standard chemotherapy drugs. They affect specific parts of cancer cells that make them different from normal cells. Several targeted therapy drugs are already used to treat advanced colorectal cancer. Researchers are studying the best way to give these drugs and looking for new targeted therapy drugs. Some new targeted drugs being studied are described below:

Most colorectal cancers that have spread are tested for common gene mutations in the KRAS, NRAS, and BRAF genes. If there are no mutations, then certain targeted drugs might be treatment options. If a colorectal cancer has a specific mutation in the BRAF gene, called BRAF V600E, then the targeted drugs cetuximab and panitumumab might be helpful if given along with targeted drugs called BRAF inhibitors and MEK inhibitors. These inhibitors are approved to treat some melanoma skin cancers, non-small cell lung cancers, and a few others. Cancers that have the BRAF V600E mutation make up about 5-10% of colorectal cancers and often have a poor prognosis (outcome). More studies are being done to find out the best combination of drugs for cancers with this mutation.

Some colorectal cancers that don’t have mutations in the KRAS, NRAS or BRAF genes, might make too much of the HER2 protein or HER2 gene. For these cancers, treatment with the targeted drugs trastuzumab and lapatinib or trastuzumab or pertuzumab might be an option. These drugs are approved for treatment in breast cancer and a few other cancers, but more research is needed for its use in people with colorectal cancer.

If a colorectal cancer doesn’t have mutations in the KRAS, NRAS or BRAF genes, it might be tested for changes in one of the NTRK genes. These gene changes can lead to abnormal cell growth and cancer. Larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) are targeted drugs that disable the proteins made by the abnormal NTRK genes. The number of colorectal cancers that have this mutation is very small (less than 1%) but this may be an option for some people.

From: www.cancer.org