When Karen Lynch was diagnosed with breast cancer at age 44, it was a shock, but not a complete surprise. “My family history is just riddled with cancer; my father had prostate cancer and died from stomach and esophageal cancer, and his five sisters passed from breast cancer,” she says. “My mother died from pancreatic cancer.” It was 1996, and genetic testing was not as routine as it is now, so it wasn’t until nine years after her diagnosis and treatment with lumpectomy and radiation that Lynch learned she carried the BRCA1 mutation, which increases her risk of breast cancer and ovarian cancer. She decided to have a bilateral mastectomy and hysterectomy to reduce her risk of having a recurrence or a new cancer in her ovaries.
“I had no problem with the hysterectomy, since I was 54,” says Lynch, who lives in Glenolden, Penn. and works as a paralegal. “But it was hard to wrap my head around having a preventive mastectomy, even though my doctors said it was not a case of, ‘will’ you get breast cancer again, but ‘when.’’” After three years of consideration and research, Lynch had the surgery, knowing it was her best chance to avoid getting cancer again and to live a long, healthy life.
But she is eager to do more. In January, she joined a groundbreaking study at Penn Medicine, where she is treated, to test a vaccine that could potentially prevent breast cancer from recurring. “If there is something out there like a vaccine that will prevent me from having cancer again, and, more importantly, help my children—it was an easy decision,” she says of joining the trial. “I’m hoping that this is something that works so my children can have this vaccine and won’t have to worry about this devastating disease.”
Vaccines are often called the miracle of modern medicine for their ability to target the immune system against disease-causing viruses and bacteria. Since they work against infectious diseases, why not against other conditions that have long plagued humanity—like cancer?
“To say that we are working on a vaccine to prevent cancers for the rest of people’s lives sounds like something from Star Wars,” says Dr. Robert Vonderheide, director of the Abramson Cancer Center at Penn Medicine. “But it’s not a concept that’s totally uncharted.”
Vaccines for cancer already exist. Human papillomavirus (HPV) vaccines, for example, largely prevent cervical cancer by targeting the HPV strains that trigger tumor growths. But most types of cancer aren’t caused by viruses, so the holy grail would be to train the body to recognize tumor cells instead. Researchers have been investigating ways to do this, starting with immunizing people who have already developed cancer in order to reduce their risk of recurrences. Improvements in the accuracy and speed of genetic sequencing have provided a clearer window into what makes cancer cells start to grow abnormally, and new drug therapies that target those genetic changes have also transformed the way doctors treat the disease. For instance, recently developed treatments can teach the immune system to seek out and destroy cancer cells.
To date, however, these immunotherapy treatments have been focused mostly on patients with advanced disease that has spread throughout their bodies, and vaccines to target those widespread cancer cells have generally been a last-resort effort to control the disease. Such therapeutic cancer vaccines remain a work in progress, but their limited success, along with new understanding of the genetic drivers behind cancer growth, have made the idea of a vaccine that could actually prevent cancer more realistic.
Increasingly, scientists are using vaccines to treat cancer earlier, and they have started to score some victories in training the immune system to attack lung, skin, and kidney cancers to prevent them from emerging again in recovered patients.
Those strategies, however, haven’t worked as well with breast cancer. “A lot of breast tumors do not attract the immune system, so there is very little in the way of an immune response,” says Vonderheide. “That’s where vaccines come in, because they are designed to start an immune response that can then be elaborated.”
Vonderheide and others are looking to use vaccines in their truest function: to optimize the immune response against cancer by training cells to recognize tumors as foreign. Once that happens in breast cancer, Vonderheide says it may be possible to not only prevent recurrences in people who have already had cancer, like Lynch, but to even protect people from developing the cancer in the first place.
A breakthrough like that can’t come soon enough, say breast cancer advocates. “I was diagnosed in 1987, and I wasn’t treated much differently from what is available today, in terms of surgery and chemotherapy,” says Fran Visco, president of the National Breast Cancer Coalition, an advocacy organization. “Yes, there is a lot of focus on immunotherapy, and that’s exciting from a research perspective. But it hasn’t really made a difference in women’s lives yet.”
While rates of breast cancer in the U.S. had been holding steady in recent decades, beginning in the 2000s, they started inching upward again by about 0.5% a year. Breast cancer accounts for a third of cancer cases in women and kills 43,000 people annually.
To make an immediate impact on people’s lives, says Visco, “we believe that a vaccine approach is certainly the key in preventing people from getting breast cancer to begin with.”
“The whole idea, just like with an infectious disease vaccine, is to identify what’s foreign in the tumor as much as possible and to craft a vaccine that targets what’s foreign,” says Keith Knutson, an immunologist at Mayo Clinic, who along with his colleagues is testing this type of preventive vaccine. “That’s where we’re going to see the power of the immune response in shrinking or preventing cancer.”
That’s easier said than done, however, and this type of vaccine may be at least a decade or so away. Cancer cells are normal cells that have picked up aberrant genetic messages to start dividing out of control. Targeting them may make intuitive sense, but it’s very difficult to identify the specific abnormalities that cancer cells pick up, since they’re often tightly woven with non-cancerous features, like receptors and other proteins the normal cell needs. Early attempts in recent decades to target such cancer-specific proteins proved disappointing.
But more sophisticated analyses of tumor cells’ genetic makeup is providing clues about which proteins on the surface of these cells are uniquely cancerous, and which are not. Armed with that knowledge, scientists have a better chance of training people’s immune systems to recognize and target those “foreign” cancer markers, just as they would a new virus.
Next spring, researchers at the Cleveland Clinic will start enrolling women with early stages of triple negative breast cancer—one of the most aggressive forms—to receive a vaccine so their immune responses can reduce their chance of developing advanced disease. The disease is named triple-negative because the cancer cells lack three of the main proteins that current treatments target, making it hard to treat. Ultimately, the doctors hope to treat women at high risk of the disease, but who have not yet been diagnosed, with a vaccine to lower their chances of getting cancer.
At the Mayo Clinic, Knutson and Dr. Amy Degnim, professor of surgery at Mayo, began working on a breast cancer vaccine in 2015, focused on the other end of the breast cancer spectrum. They recently began testing it in women with an early form of breast cancer called ductal carcinoma in situ, or DCIS. Experts have debated in recent years whether DCIS is actually cancer, since it involves lesions that remain in the ducts of the breast tissue and don’t spread throughout the breast, as other forms of breast cancer do. About 51,000 women in the U.S. are diagnosed with DCIS each year, and some of those cases will become cancerous—although doctors can’t predict which ones. “There’s quite a bit of evidence that a lot of DCIS may not progress to become invasive cancer, but we don’t know for any individual patient if that’s true or not,” says Degnim. Many women with the condition therefore opt to have radiation and surgery to remove the lesions to avoid the risk of developing cancer. If the immune system could be trained to attack DCIS, “maybe we can scale back our treatments,” Degnim says.
Degnim and her team began testing the vaccine by giving it to people with advanced breast cancer first, targeting a specific protein called HER2 that is found on the surface of 20% of all breast cancers and is more common in DCIS. The encouraging immune responses they saw in that study justified trying the approach in women earlier in the disease process.
Now, in a trial that began in 2019, the team is giving about 43 women with DCIS one of three vaccine doses. All of the women will then be treated with surgery to remove their DCIS, and Degnim and Knutson will evaluate the lesions for any signs of immune response. They will also take blood samples to determine if the patients mounted an immune response against the DCIS—and if so, how much of one.
Other recent advances have also nudged researchers one step closer to a truly preventive breast cancer vaccine. Scientists have gained a more detailed view of how, exactly, tumors co-opt the immune system. It turns out that while cancer cells start to grow uncontrollably, they protect themselves from immune cells by throwing up a wall of protection to disguise their presence. That immune suppression acts like a force field, allowing tumors to continue growing and spreading undetected from one tissue to another.
But in 2015, doctors developed a powerful way to break down that tumor wall. Drugs called immune checkpoint inhibitors effectively rip off cancer cells’ disguise and expose them for the immune system to see and attack. Combining these drugs with a vaccine that targets the right cancer features represents new hope in immunizing people against cancer. “I think the first opportunity that we’re going to see some kind of vaccine approved is probably going to be in combination with an immune checkpoint inhibitor in people with advanced cancer,” says Knutson. “We’re going to be able to look in real time if the tumor is shrinking, and that’s going to answer—much faster—the question of how effective the vaccine might be.”
The proteins covering breast cancer cells aren’t the only targets for a cancer vaccine. So is the DNA of breast cancer cells. The most successful COVID-19 shots, from Moderna and Pfizer-BioNTech, used genetic material in the form of mRNA from the SARS-CoV-2 virus to build immunity, and scientists think a similar approach, using the genetic material DNA, could work for breast cancer.
Lynch is hoping such vaccines can change the course of breast cancer, if not for her then for future generations. One of her daughters, who also has the BRCA1 mutation, was diagnosed with breast cancer at age 26 and opted to have both breasts removed. Because of her young age, she also underwent fertility treatments to improve her chances of later getting pregnant. “I want my children and their children to be safe from this disease,” Lynch says. In February, Lynch joined the trial at Penn Medicine conducted by Dr. Susan Domchek to explore the safety of a vaccine targeting an enzyme, called telomerase, that breast cancer cells use to regulate how many times they divide. The enzyme is most active in cells that are aggressively dividing, such as cancer cells, and less active in normally functioning cells. A vaccine including snippets of DNA coding for key parts of telomerase trains a group of immune cells in the body known as T cells to recognize and target cancer cells that are using too much telomerase. They “stalk the blood to attack and kill those [cancer] cells before anyone even knew they were there,” says Domchek. Vonderheide, who is collaborating with Domchek on the trial, says that training the T cells against cancer could be critical to making an effective breast cancer vaccine. “We think the best vaccines for cancer will be those that generated T cells,” he says, because those responses could last longer and ultimately generate a surge of immune cells that could more immediately recognize and eliminate cancer cells. The study is part of Penn’s new Basser Cancer Interception Institute, which is focused on intervening in BRCA1 and BRCA2 cancers as early as possible to alter the normal progression of disease.
The team at Penn Medicine is currently enrolling 16 people who, like Lynch, have been diagnosed with cancer and who have the genetic mutations BRCA1 or BRCA2, which put them at higher risk of developing breast cancer, to see if vaccinating them will lower their chance of recurrence. The researchers also plan to study 28 people with the genetic risk—but who have not yet been diagnosed with cancer—to see if the vaccine could lower their risk of developing the disease. Lynch has completed her four injections and will provide blood for Domchek and her team to study every 16 weeks for nearly two years.
If the vaccine can show decreased risk of recurrence, or a significantly reduced risk of developing cancer at all, says Domchek, “it’s a game changer.” Currently, doctors recommend that women who carry the BRCA mutations get screened throughout their lives for any lesions, and, if found, to undergo surgery; some women even elect to have a preventative mastectomy as a way to avoid developing cancer. BRCA mutations also put women at higher risk ovarian cancer, and because there is no effective way to screen for that disease, some women decide to have their ovaries removed, which triggers early menopause. “We have not had great options, apart from surgical options, for women with BRCA mutations,” Domchek says. “But this concept of being able to use the immune system to change the natural history for these people is so critical.”
A lot is riding on the outcomes of these trials, but scientists are cautiously optimistic that breast cancer care will look markedly different over the next few years—and that vaccines for cancer will move away from treating advanced disease to making a difference at earlier stages. “I think we are probably at the end of the era of using cancer vaccines with great hope in a patient who has already been treated with everything,” says Vonderheide, “to using these vaccines in people who are at risk of relapse, or in individuals who are simply at high risk for cancer and want to prevent it. Prevention and survivorship is what cancer is going to be about in 10 years, and I think vaccines will play a part in ensuring that’s the case.”
Lynch is counting on that. Her aunt was diagnosed with breast cancer that recurred 25 years later and spread to the brain. Lynch’s goal was to survive at least that long without cancer, and this October, she surpassed that milestone. “I wanted to be a 26-year survivor,” she says. “I made it, and I want to make it even longer.”
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Contributor: Alice Park