A Fast Track for Cancer Vaccines

THE CORONAVIRUS PANDEMIC ​has disrupted ordinary life, the economy and health care to an unprecedented degree for more than a year. It has generated an equally unprecedented investment of time, money and expertise to mobilize health care efforts. The genetic code for SARS-CoV-2, the virus that has now killed millions of people worldwide, was first reported by Chinese authorities in January 2020, and clinical trials for the first COVID-19 vaccines were launched within two months. As of May 30, 2021, nearly 168 million people in the U.S. had received at least one dose of one of the three COVID-19 vaccines that received emergency use authorization from the Food and Drug Administration (FDA).

This rollout occurred over an astonishingly short time period in the world of pharmaceutical development. For comparison, the first effective Ebola vaccine, which was approved in December 2019, required nearly two decades of intense effort. New cancer treatments typically require a decade or more to get from discovery to patients.

Both of the first two COVID-19 vaccines authorized for emergency use harness an approach that has never previously been used successfully to save lives. The vaccines are built using genetic material called messenger RNA (mRNA), which is produced in a laboratory following the genetic instructions from the coronavirus. Messenger RNA provides the blueprint for building molecules that can trigger an immune response. Even though COVID-19 is new, mRNA vaccine technology has been years in the making—largely driven by researchers developing next-generation therapies for people diagnosed with cancer.

“It seems like these vaccines have almost come out of nowhere, but these mRNA vaccines are actually coming on the back of 10 years or more of research into cancer vaccines,” says Jessica McCormack, an oncology and hematology analyst with GlobalData, a consulting and data firm in London. The German biotechnology company BioNTech, for example, which partnered with Pfizer to develop one of the new COVID-19 vaccines, was founded in 2008 to develop cancer vaccines.

The COVID-19 vaccines are designed to spur the immune system to target the coronavirus, but an mRNA vaccine for cancer, in theory, could be customized to induce an immune response to an individual’s tumor. It’s too soon to know if mRNA vaccines will succeed as cancer treatments, but clinical trials have been launched to find out. “We can’t declare a home run,” says thoracic oncologist Leena Gandhi, director of the Center for Cancer Therapeutic Innovation at Dana-Farber Cancer Institute in Boston. She is working on and recruiting for a multi-institutional, phase I clinical trial that combines an mRNA cancer vaccine with the immunotherapy drug Keytruda (pembrolizumab) for patients with lung, colorectal and other cancers. “But if we can get good responses from this approach, what the COVID vaccine has demonstrated is that you can probably accelerate development.”

Why mRNA Is Appealing

The vaccines for COVID-19, like those for measles, mumps and polio, are preventive, which means they can prevent or lessen a serious infection by a virus. The FDA has approved a few vaccines to prevent the development of cancer, including ones to protect against human papillomavirus infection, which causes cervical and anal cancer and some vaginal, penile, vulvar and head and neck cancers, and hepatitis B infection, which can lead to liver cancer. But the research into mRNA cancer vaccines focuses on therapeutic applications, which means they’re designed to benefit people already diagnosed with cancer.

Researchers have been attempting to harness the immune system to treat cancer for at least 120 years. In one of the pioneering efforts, physician William Coley in New York City tried to stimulate the immune system of a patient known to history only as Zola, who had a life-threatening tumor the size of a hen’s egg in his throat. Coley injected pathogenic bacteria called Streptococcus pyogenes into Zola’s tumor. The patient initially fell ill, but after he recovered, the tumor shrank, and he could swallow again.

Coley’s work was an early example of cancer immunotherapy, which has the goal of harnessing the strength of the body’s own immune system. Immunotherapy has joined chemotherapy, radiation, targeted therapy and surgery as a potent treatment option for patients, though immunotherapy is not used as widely. It also led to the development of the BCG vaccine (for Bacillus Calmette-Guérin), a vaccine for tuberculosis that can also be given to patients with early-stage bladder cancer and, as in Coley’s approach, stimulates the immune system with infectious bacteria.

More recently, the FDA has approved immunotherapeutic cancer treatments, including checkpoint inhibitors, which essentially release the brakes on the body’s natural defenses, and CAR-T cell therapy, in which a patient’s T cells are harvested, genetically modified and then injected back into the body to boost the immune response. The FDA has also approved a vaccine called Provenge (sipuleucel-T), which uses a patient’s own cells to treat prostate cancer.

But an mRNA vaccine would be different from any of these existing immunotherapies, largely because of its potential adaptability to a wide range of diseases, stages and people. The key to that adaptability is the mRNA itself.

In human cells, mRNA is a molecule that carries genetic information from one place to another. In a cell, DNA, coiled up in the nucleus, encodes the biological blueprints for proteins required for the cell to do its jobs. The mRNA, which is a single-stranded spiral, “copies” the blueprints from the DNA and carries them to the ribosomes, which make the proteins.

The first two approved COVID-19 vaccines both contain molecules of mRNA that encode the instructions for assembling a piece of a certain viral protein, called the “spike,” which the coronavirus uses to invade a host cell. The vaccines don’t contain the actual virus, though, which means they can’t cause an infection. As a result, a person injected with the vaccine produces those telltale spike proteins, but not the entire virus. The proteins trigger the body’s immune system to produce defensive antibodies and other immune responses against the proteins. Via this method, the body is primed to defend itself from an actual infection by SARS-CoV-2 should it occur.

There is no reason why this approach should work only for the spike protein, says Gandhi. In theory, an mRNA vaccine could teach a person’s immune system to recognize the genetic signatures of cancerous cells. “Essentially, by changing the coding sequence you can reprogram [the immune system] to attack anything you like,” she says.

An mRNA vaccine could be custom-made to match the genetic signature of an individual’s cancer. It could also potentially be fashioned as a more general vaccine that might help a larger swath of people. Such a “universal” vaccine would include mRNA associated with frequent mutations known to drive the growth of cancer.

“If you had that type of vaccine on the shelf, you could use it quickly to treat patients,” says gynecologic oncologist Hans Nijman at the University Medical Center Groningen in the Netherlands, who is leading a phase I clinical trial for an ovarian cancer vaccine developed by BioNTech.

Drug companies are ramping up their efforts. Ugur Sahin and Özlem Türeci, the married cancer researchers who started BioNTech, began their company with a focus on new cancer treatments, which before the pandemic was their primary focus. “Developing this pipeline for cancer patients is what allowed them to quickly pivot to a COVID-19 vaccine,” says Nijman.

In January 2021, Cambridge, Massachusetts-based drug company Moderna Therapeutics, which also developed an mRNA COVID-19 vaccine, announced it had begun work on new vaccines for the flu, HIV and Nipah virus. The company is also pursuing​ personalized cancer vaccine research, which produces custom-made vaccines based on the antigens—proteins that can start an immune response—detected in a person’s own cancerous cells.

“The beauty of the mRNA approach is that you can use several different antigens within the same vaccine approach,” says Nijman.

Caution Signs

The growing optimism among cancer researchers inspired by the COVID-19 vaccines is tempered by a sober acknowledgment of the past. “Generally, vaccines have been met with very low enthusiasm” by researchers looking for new treatments, says McCormack. Dozens of clinical trials have tested mRNA vaccines on a variety of cancer types, but without any clear successes in extending survival or helping patients. In one notable example in 2017, after a lengthy and expensive development process, a prostate cancer mRNA vaccine developed by the Dutch and German company CureVac failed to extend patient lives in a phase II clinical trial.

One reason cancer vaccines will require more time to develop than those for COVID-19—or other diseases caused by viruses—is that cancers arise from mutations in cells, not from infectious pathogens. “Tumors are derived from your own body cells that have become abnormal,” says Gandhi. “They’re a lot more complicated. The hard thing about cancer is that it’s always been a much harder problem to attack than a virus.”

Tumors vary from person to person. They’re also heterogeneous, which means that a single tumor comprises a sprawling mix of different types of cells. As a cancer evolves, it can amass thousands of genetic mutations, and very few of those mutations produce targetable, tumor-specific neoantigens—proteins resulting from mutations—that could be used as the backbone of an mRNA vaccine. In addition, the mRNA used in a vaccine may not spur an immune response sufficient to inhibit the growth of a tumor.

“Out of 10 tumor cells, if eight are knocked down and two aren’t, then those two will survive and grow out again,” says Nijman of the challenges faced in using mRNA vaccines against cancer.

On top of that, says Leaf Huang, a professor of molecular pharmaceutics at the University of North Carolina in Chapel Hill, is the issue of the microenvironment—the tissue neighborhood where cancer grows. In recent years, he says, studies have shown how cancerous cells change their surroundings to help keep the immune system away. Even if researchers can identify potent neoantigens for mRNA vaccines, he says, they still have to find a way to remodel the surrounding environment to allow T cells access to the tumor.

A third major challenge is the nature of cancer itself. The COVID-19 vaccine trains the body to neutralize a single viral particle, and once that’s done, the disease is no longer a threat. In cancer, attacking a single target may not benefit patients, says Gandhi. “That wouldn’t necessarily result in cancer regression.” Even faced with vaccines targeting neoantigens, cancers have ways of evading and tamping down the immune response, Gandhi says. It’s unlikely that a single mRNA vaccine, whether personalized or universal, could keep new malignancies away indefinitely.

The Way Forward

To overcome some of these challenges, recent clinical trials have been pairing experimental mRNA vaccines with chemotherapy, immunotherapy or radiation. Gandhi is a principal investigator for a phase I clinical trial testing a new vaccine from Moderna that targets the neoantigens produced by four common mutations in KRAS, a well-known genetic driver for colorectal, lung and pancreatic cancers. (Patients with advanced or metastatic disease—including those three cancer types—are being recruited for the trial.) Once inside a person’s body, the mRNA in the vaccine would coax healthy cells to produce neoantigens just like the ones produced by cancer cells with one of the four KRAS mutations—and be readily identified for attack by T cells, which recognize and kill cellular targets by recognizing antigens on their surface.

To increase the chance of success, the researchers have paired the vaccine with Keytruda, an immune checkpoint inhibitor. (The trial is a collaboration between Merck, which makes Keytruda, and Moderna, which produces the vaccine.) The researchers hope for a one-two punch: Keytruda maintains the immune response in the tumor, and the vaccine stimulates the production and proliferation of T cells.

In the Netherlands, Nijman has been collaborating for nearly a decade with BioNTech to identify neoantigens that could be used in vaccines. The phase I trial of the BioNTech ovarian cancer vaccine that Nijman is leading pairs the mRNA vaccine with chemotherapy to capitalize on the benefits of both approaches.

Huang, in North Carolina, notes that administering an mRNA vaccine and low-dose radiation together could strengthen the immune response against the tumor. For example, a recent phase I cl​inical trial tested whether radiation can bolster the efficacy of an mRNA vaccine under development by CureVac in people with metastatic non-small cell lung cancer. The vaccine uses mRNA that causes cells to produce six neoantigens associated with mutations in non-small cell lung cancer. Results from a small phase I trial, published in 2019, suggest the combination is safe and may be effective for some patients.

Right now, it’s not clear which combinations, if any, will successfully overcome the biological challenges facing the use of mRNA vaccines to treat cancer. But if researchers can develop a cancer vaccine that benefits patients, then the path to approval will be short, predicts Nijman, because of the COVID-19 vaccines. “What the pandemic has shown with respect to mRNA vaccines is that personalized medicine for patients is really an option,” he says.

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