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Dr Catherine Wu
Finding a cure for cancer is a motivating force for many an aspiring doctor. Few get anywhere close to pursuing that goal. Among them is Dr. Catherine Wu, an oncologist at Bostons Dana-Farber Cancer Institute, who has had cancer in her sights since second grade, when a teacher asked her and her classmates what they wanted to be when they grew up.
Thats when there was a lot of coverage on the war on cancer, she said.I think I drew a picture of a cloud, probably a rainbow and drew a picture of (me) like, making a cure for cancer or something like that.
That childhood scribble was prescient. Wus research has laid the scientific foundation for the development of cancer vaccines tailored to the genetic makeup of an individuals tumor. Its a strategy looking increasingly promising for some hard-to-treat cancers such as melanoma and pancreatic cancer, according to the results of early-stage trials, and may ultimately be widely applicable to many of the 200 or so forms of cancer.
The Royal Swedish Academy of Sciences, which selects Nobel laureates in chemistry and physics, last week awarded Wu its Sjöberg Prize in honor of decisive contributions to cancer research.
Cancer treatment has progressed over the years but there are still sort of a lot of unmet medical (needs) out there for many cancer forms, said Urban Lendahl, professor of genetics at the Karolinska Institutet in Sweden and the secretary of the committee that awarded the prize.
Sledgehammer cancer treatments
The most common treatments for cancer - radiation therapy and chemotherapy - are like sledgehammers, striking all cells and often damaging healthy tissue. Since the 1950s, cancer researchers have been seeking a way to dial up the bodys immune system, which naturally tries to fight cancer but is outsmarted by it, to attack tumor cells.
Progress on that front was middling until about 2011 with the arrival of a class of drugs called checkpoint inhibitors, which boost the anti-tumor activity of T cells, an important part of the immune system. The work led to the 2018 Nobel Prize for medicine for Tasuku Honjo and James Allison, the latter a winner of the 2017 Sjöberg Prize.
These drugs have helped some people with cancer who would have been given months to live survive for decades, but they dont work for all cancer patients, and researchers continue to look for ways to turbocharge the bodys immune system against cancer.
Wus fascination with the powers of the immune system arose after witnessing bone marrow transplants as a medical intern and seeing how they rebooted the blood and immune system to fight cancer.
I had had really formative academic experiences that made me quite interested in the power of immunology, she said. There in front of my eyes were people who are being cured of their leukemia because of the mobilization of immune response.
Wus research focused on small mutations in cancer tumor cells. These mutations, which occur as the tumor grows, create proteins that are slightly different to those in healthy cells. The altered protein generates whats called a tumor neoantigen that can be recognized by the immune systems T cells as foreign, and therefore susceptible to attack.
With thousands of potential neoantigen candidates, Wu used tour de force lab work to identify the neoantigens that are on the cell surface, making them a potential target for a vaccine, Lendahl said.
If the immune system is to have a chance to attack the tumor, this difference must be manifested on the surface of the tumor cells. Otherwise, its pretty pointless, Lendahl added.
˜A fantastic discovery
The idea of a cancer vaccine has been around for decades. The widely used HPV vaccine targets the virus that is linked to an increased risk of cervical, mouth, anal and penile cancer. However, in many cases, cancer vaccines have failed to live up to their promise - largely because the right target hasnt been found.
The ability to identify neo-specific tumor antigens has really developed into a large field of cancer research, as it offers the possibility to generate tumor-specific cancer vaccines, Hans-Gustaf Ljunggren, a professor of immunology at the Karolinska Institutet, said in a video shared by the Royal Swedish Academy of Sciences. This is a fantastic discovery.
By sequencing DNA from healthy and cancer cells, Wu and her team identified a cancer patients unique tumor neoantigens. Synthetic copies of these unique neoantigens could be used as a personalized vaccine to activate the immune system to target the cancer cells.Wu and her team wanted to test this technology in advanced melanoma patients in a trial.
The Idea that every patient involved in the trial would get an individualized vaccine was initially hard for the US Food and Drug Administration, which regulates clinical trials, to wrap its collective head around, Wu said. Typically, the FDA would require the vaccines to be tested first in animal experiments.
Wu and her team made their case: That room was packed. 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 in an animal doesnt really match the human - so why even go that route?
Several cancer vaccine trials are now underway but they are small-scale. More work is needed before they are a viable treatment options for many cancer patients.
Once it had FDA approval, the team vaccinated six patients with advanced melanoma with a seven-shot course of patient-specific neoantigens vaccines. The breakthrough results were published in an 2017 article in Nature. For some patients, this treatment resulted in the immune systems cells being activated and targeting the tumor cells. The results, along with another paper published the same year led by the founders of mRNA vaccine company BioNTech, provided proof of principle that a vaccine can be targeted to a persons specific tumor, Lendahl said.
A follow-up by Wus team four years after the patients received the vaccines published in 2021, showed that the immune responses were effective in keeping cancer cells under control.
Im grateful for all the patients that participated in our trial because they are ¦ active partners, Wu said. Its hard enough to go through treatment, but then to go through treatment that is of unknown benefit, and to be able to be willing to come in for all the extras that we need to do this type of research. There are more tests, there are more blood draws, there are more biopsies.
Since then, Wus team, other groups of medical researchers and pharmaceutical companies, including Merck, Moderna and BioNTech, have further developed this field of research, with trials underway for vaccines that treat pancreatic and lung cancer as well as melanoma.
Unanswered questions
All the trials underway are small-scale, typically involving a handful of patients with later-stage disease and a high tolerance for safety risks. To show that these type of cancer vaccines work, much larger randomized control trials are needed.
The numbers are small, I mean, for obvious reasons, Lendahl said. Data (looks) encouraging, but its still of course, early days.
Scientists are also figuring out the most effective way to format the vaccines. Wus group and others have used vaccines made from peptides or strings of proteins. Moderna and BioNtech use mRNA, which the companies pioneered in developing vaccines against Covid-19, to deliver a set of instructions to cells to make the relevant proteins.
My belief is that there are many roads to Rome. I think theres many different delivery modalities, but each delivery approach can be optimized with different bells and whistles, Wu said. There has to be investment in and how to make that delivery approach work the best. And right now theres a huge appetite for mRNA you know, fed by our pandemic.
Cancer vaccines have shown the most promise in what oncologists colloquially term hot tumors that mutate quickly, such as melanoma that was Wus initial focus.Its not clear whether they will be effective against cold tumors such as breast cancer, which are more inert.
Its easier if there (are) spontaneously more mutations occurring in the tumor because youve got a better smorgasbord of potential small molecules to choose from for making your vaccine, Lendahl said.
Another challenge is how to manufacture these vaccines in a more cost-effective and time-sensitive way so they can reach large numbers of cancer patients, Wu said. Right now, it can take weeks, if not months, to make the individualized vaccines at a cost of hundreds of thousands of dollars. An active avenue of research is developing vaccines that target neoantigens that are shared by patients with the same cancer type, raising hope for an off-the-shelf vaccine, which many people could use without a lengthy personalization process.
Another question is whether the vaccines will work best in combination with other treatments to make them a sharper tool and, if so, which ones.
The results of a trial published late last year found that a vaccine, developed by Merck and Moderna, given to patients with advanced melanoma along with a type of immunotherapy called Keytruda, a drug based on checkpoint inhibitors, led to a lower risk of recurrence or death than those who got the drug alone, the companies said.
Its also not known at what point in the treatment cycle will vaccines be most useful - treating cancers caught early, helping patients with advanced disease or ensuring patients remain cancer-free. Most trials underway involve patients with late-stage cancer or patients in remission, but Wu said she thinks vaccines may be more effective in early-stage disease.
Despite the laundry list of unknowns, for some involved in these early cancer vaccine trials, the results have been life-changing.
I am just so grateful to have been allowed to take it, Barbara Brigham, who received a personalized vaccine for pancreatic cancer being tested by BioNTech, told CNN last year. She was able to watch her oldest grandchild graduate from college - a moment she didnt think she would live to see. The opportunity and timing was so perfect, she said. It helped me, and I hope it helps someone else. (CNN)
