The idea of a cancer vaccine has existed for decades. But now there is a discovery that allows us to dream of the possibility of generating specific cancer vaccines for each tumor.
The doctor behind the next big thing in cancer treatment
per Katie HuntCNN
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Finding a cure for cancer is a motivating force for many aspiring doctors. Few come close to achieving this goal. Among them is Catherine Wu, an oncologist at the Dana-Farber Cancer Institute in Boston, USA, who has had her sights set on curing cancer since second grade, when a teacher asked her and her classmates what they wanted to be when they grew up. .
“That was when there was a lot of coverage about the war on cancer,” he says. “I think I drew a picture of a cloud, probably a rainbow, and I made a picture where I imagined myself creating a cure for cancer or something like that.”
This childhood doodle was prescient. Wu’s research laid the scientific foundation for developing cancer vaccines tailored to the genetic makeup of each individual’s tumor. It’s a strategy that appears increasingly promising for some difficult-to-treat cancers – such as melanoma and pancreatic cancer, according to results from early-stage trials – and which could prove to be broadly applicable to many of the nearly 200 forms of cancer.
The Royal Swedish Academy of Sciences, which selects Nobel Prize laureates in Chemistry and Physics, awarded the Sjöberg Prize to Wu in honor of his “decisive contributions” to cancer research.
Cancer treatment “has progressed over the years, but there are still many unmet medical needs for many forms of cancer,” says Urban Lendahl, professor of genetics at Karolinska Institutet in Sweden and secretary of the committee that awarded the prize.
Cancer treatments
The most common treatments for cancer – radiotherapy and chemotherapy – are like sledgehammers, hitting every cell and often damaging healthy tissue. Since the 1950s, cancer researchers have been looking for a way to activate the body’s immune system, which naturally tries to fight cancer but is overtaken by it, to attack tumor cells.
Progress on this front was average until 2011, with the arrival of a class of drugs called “checkpoint inhibitors”, which increase the anti-tumor activity of T cells, an important part of the immune system. The work led to the awarding of the 2018 Nobel Prize for Medicine to Tasuku Honjo and James Allison, the latter of whom was awarded the 2017 Sjöberg Prize.
These drugs have helped some people with cancer who had months to live survive for decades, but they don’t work for all cancer patients — and researchers continue to look for ways to boost the body’s immune system against cancer.
Wu’s fascination with the powers of the immune system came after witnessing bone marrow transplants as a medical intern and seeing how they reset the blood and immune system to fight cancer.
“I had really formative academic experiences that made me really interested in the power of immunology,” he says. “Before my eyes were people who were being cured of leukemia due to the mobilization of the immune response.”
Wu’s research focused on small mutations in cancerous tumor cells. These mutations, which occur as the tumor grows, create proteins that are slightly different from those in healthy cells. The altered protein generates what is called a “tumor neoantigen”, which can be recognized by the T cells of the immune system as foreign and, therefore, susceptible to attack.
With thousands of potential neoantigen candidates, Wu turned to “task force laboratory work” to identify the neoantigens that lie on the surface of cells, making them a potential target for a vaccine, says Lendahl.
“For the immune system to be able to attack the tumor, this difference has to manifest itself on the surface of the tumor cells. Otherwise it is useless,” added Lendahl.
“A fantastic discovery”
The idea of a cancer vaccine has existed for decades. The widely used HPV vaccine targets the virus that is associated with an increased risk of cancer of the cervix, mouth, anal canal and penis. However, in many cases, cancer vaccines have failed to deliver on their promise – largely because the right target has not been found.
“The ability to identify neospecific tumor antigens has developed into a vast field of cancer research, as it offers the possibility of generating tumor-specific cancer vaccines,” says Hans-Gustaf Ljunggren, professor of immunology at Karolinska Institutet , in a video shared by the Royal Swedish Academy of Sciences. “This is a fantastic discovery.”
By sequencing the DNA of healthy and cancerous cells, Wu and his team identified the unique tumor neoantigens of a cancer patient. Synthetic copies of these unique neoantigens could be used as a personalized vaccine to activate the immune system and target cancer cells. Wu and his team wanted to test this technology in patients with advanced melanoma in a trial.
The idea that all patients involved in the trial would receive an individualized vaccine was initially difficult for the US Food and Drug Administration, which regulates clinical trials, to accept, explains Wu. Normally, the FDA would require that vaccines be tested in animal experiments first.
Wu and his team defended their position: “The room was full. It was the first trial of its kind and there were people from many different offices. Our argument was ‘this is personalized, whatever we do to an animal doesn’t really match the human – so why go down that path?'”.
After obtaining FDA approval, the team vaccinated six patients with advanced melanoma with a seven-dose course of patient-specific neoantigen vaccines. The groundbreaking results were published in a 2017 article in the journal Nature. For some patients, this treatment caused immune system cells to activate and attack tumor cells. The results, along with another paper published the same year led by the founders of the mRNA vaccine company BioNTech, provided “proof of principle” that a vaccine could be targeted to a person’s specific tumor, says Lendahl.
A follow-up by Wu’s team four years after patients received the vaccines, published in 2021, showed that immune responses were effective in keeping cancer cells in check.
“I am grateful for all the patients who participated in our study because they are active partners,” says Wu. “It’s hard enough to go through treatment, but then to go through treatment whose benefit is unknown and be willing to participate in all the extras we need to do this kind of research… There are more tests, more blood draws, more biopsies…”
Since then, Wu’s team, other groups of medical researchers and pharmaceutical companies – including Merck, Moderna and BioNTech – have been developing this field of research, with trials underway for vaccines that treat pancreatic and breast cancer. lung, as well as melanoma.
Unanswered questions
All ongoing trials are small-scale, typically involving a handful of patients with advanced-stage disease and a high tolerance for safety risks. To demonstrate that these types of cancer vaccines work, much larger randomized control trials are needed.
“The numbers are small, for obvious reasons,” says Lendahl. “The data looks encouraging, but it’s clear that these are still early days.”
Scientists are also discovering the most effective way to format vaccines. Wu’s group and others have used vaccines made from peptides or protein chains. Moderna and BioNtech use mRNA – these are pioneering companies in developing vaccines against Covid-19 – to provide a set of instructions to cells to produce the relevant proteins.
“My belief is that there are many paths to Rome. I think there are many different governance modalities, but each governance approach can be optimized with different bells and whistles,” says Wu. “There is a need to invest in how to make this delivery approach work better. And right now there is a huge appetite for mRNA, fueled by our pandemic.”
Cancer vaccines have shown most promise in what oncologists colloquially call “hot tumors,” which mutate rapidly, such as melanoma, which was Wu’s initial focus. It is not clear whether they are effective against “cold tumors”, such as breast cancer, which are more inert.
“It’s easier if there are more mutations spontaneously occurring in the tumor because you have a better variety of potential small molecules to make the vaccine,” says Lendahl.
Another challenge is how to manufacture these vaccines more cost-effectively and quickly so that they can reach a large number of cancer patients, says Wu. Currently, the production of individualized vaccines can take weeks – or months – at a cost of hundreds of thousands of euros. An active avenue of research is the development of vaccines that target neoantigens shared by patients with the same type of cancer, raising hope for an “off-the-shelf” vaccine that many people could use without a long customization process.
Another question is whether vaccines work better in combination with other treatments to make them a more effective tool, and if so, which ones.
The results of a trial published late last year revealed that a vaccine developed by Merck and Moderna, administered to patients with advanced melanoma along with a type of immunotherapy called Keytruda – a medicine based on checkpoint inhibitors – led to a lower risk of recurrence or death than those who received the drug alone, the companies said.
It is also unknown at what point in the treatment cycle vaccines are most useful – treating early-detected cancers, helping patients with advanced disease, or ensuring that patients remain cancer-free. Most of the ongoing trials involve patients with advanced-stage cancer or in remission, but Wu thinks vaccines may be more effective in the early stages of the disease.
Despite the long list of unknowns, for some people involved in these early cancer vaccine trials the results have been life-changing.
Barbara Brigham, who received a personalized pancreatic cancer vaccine being tested by BioNTech, told CNN last year: “I’m very grateful to have been allowed to take it.” She was able to attend her oldest grandson’s college graduation—a moment she didn’t think she would live to see. “The opportunity and timing were perfect,” she said. “It helped me and I hope it helps someone else.”
CNN’s Brenda Goodman contributed to this report
