Could a deadly form of breast cancer be treated with a vaccine?

A rare and deadly form of breast cancer may one day be a vaccine-preventable disease.

In recent years, researchers have been studying and testing more than 30 potential vaccines for triple-negative breast cancer (TNBC). This is an uncommon type of breast cancer that’s especially hard to treat. It’s also aggressive, which means it tends to grow and spread faster than other forms of breast cancer.

Based on early results, many of the new vaccines appear safe. But most of the trials have been small and have not yet provided the results needed to continue the path to patient care. Researchers and healthcare providers (HCPs) are hopeful that these vaccines will soon be available to treat TNBC.

Why is triple-negative breast cancer so hard to treat?

Only about 10 to 15 percent of all breast cancers are triple-negative but these cancers account for more deaths than other breast cancer types. Triple-negative breast cancer is also more likely than other breast cancers to return after successful treatment.

Black people, people younger than 40, and those who have a mutation in the BRCA1 breast-cancer gene are disproportionately affected by TNBC. Many people who learn they have such a genetic mutation choose to have a mastectomy to reduce the chances that a cancer will develop.

“Triple negative” refers to the fact that this type of breast cancer is missing three key vulnerabilities to treatment. Most breast cancer cell surfaces have receptors, like docking stations, that connect with certain hormones or proteins. These hormones include estrogen and progesterone; proteins include HER2.

If a tumor cell has any of those three receptors, the corresponding hormone or protein fuels the cancer’s growth. Certain types of targeted treatment can cut off those fuel supplies. For example, drugs designed to block hormones or interfere with the HER2 receptor can help slow those cancers’ growth.

Triple-negative breast cancer is different from other types of breast cancer in that it lacks all three receptors. That means triple-negative tumors remain unaffected by these targeted drugs. Instead, people with triple-negative breast cancers are often treated with chemotherapy and radiation. These are classic cancer treatments that target all fast-growing cells in the body, both healthy and cancerous. This blanket approach comes with many side effects and often does not cure the cancer.

Other newer types of breast cancer treatment, including targeted therapies like PARP inhibitors and forms of immunotherapy like immune checkpoint blockers (ICBs), may also be used for some patients.

What to know about clinical trials for new vaccines

When new drugs, vaccines, or treatments are developed, researchers put those treatments through a series of tests to see how well they work, typically starting with phase I.

Phase I trials are typically done to learn about the safety and side effects of the treatment. Phase II trials look at safety as well as the effectiveness of the treatment. Phase III trials are typically considered the final stage of evaluation. They are done to confirm the findings of the previous phases and to compare the treatment to standard treatments (such as chemotherapy or radiation) or to a placebo (a treatment that contains no actual medicine). (Phase IV trials track a treatment’s performance and safety after it has been approved and used by patients.)

Of the many promising vaccines for triple-negative breast cancer being developed, only about two percent of them are now moving onto phase III, according to researchers in a 2023 review in Vaccines.

One of the vaccines progressing toward a phase III trial has been developed by researchers at the Cleveland Clinic. Their early-phase trial of an experimental vaccine against triple-negative breast cancer showed promising results. Plans are underway for phase II and III studies to evaluate the vaccine’s ability to prevent recurrence of cancer in survivors and ultimately its role in preventing the initial onset of TNBC. Data were presented by researchers at the 2023 San Antonio Breast Cancer Symposium.

The vaccine is made by Anixa Biosciences, Inc, to which Cleveland Clinic has exclusively licensed the technology.

How the vaccine for triple-negative breast cancer works

The new vaccine is designed to help teach the body’s immune system to find and destroy triple-negative breast cancer cells as they are beginning to form in the breast. This is what’s known as primary prevention. (The vaccine is not intended to treat metastatic triple-negative breast cancer, or cancer that has spread beyond the original site.)

The breast cancer vaccine zeroes in on a specific protein that breast cancer cells make. This protein is not found in the normal breast cells of non-pregnant, non-lactating people. Called alpha-lactalbumin, this protein is created by the healthy breast during late pregnancy and breastfeeding only. It doesn’t reappear in the body except with breast cancers, which resurrect and pump out alpha-lactalbumin protein during early growth.

“What’s different about the vaccine, and what’s clever, is lactalbumin is a protein or a target that’s expressed in lactating women. It is not expressed on breast cells if you’re not lactating,” explains Pamela Munster, MD, a medical oncologist, expert in early cancer prevention, and professor of medicine at the University of California, San Francisco, who was not involved with the trial. “The goal with this is they will capture a target that’s only expressed in breast cancer.”

(This explains why people who are lactating are not eligible to participate in the vaccine trial.)

The vaccine teaches the immune system to detect the out-of-place alpha-lactalbumin and to destroy cancer cells that are creating it. The strategy has worked to prevent breast cancers in mice as well as to control the growth of cancers that already exist, according to a report from the research team published in a 2010 article in Nature Medicine.

“The [immune] cells, those angry lymphocytes that are out there to kill something—it’s like a guided missile, but you actually have to have a target,” Dr. Munster says.

Immunotherapy: harnessing the immune system to attack cancer

Anixa’s vaccine is an example of immunotherapy, a group of cancer treatment approaches that harness the immune system to attack cancer cells. The immune system’s main job is to fight off harmful bacteria and viruses. But it is also believed to suppress some early cancers.

When mutations in a cell’s DNA lead to its dividing over and over again, the result can be cancer. But in healthy individuals, immune cells are thought to be able to spot and stop this runaway growth, controlling or even eliminating tumor growth. This process, called immune surveillance, is why a healthy immune system is a key part of cancer prevention.

But some cancers can evade recognition by the immune system. In such cases, immunotherapy can sometimes help guide the immune system’s “attention” to the cancer or help unleash its innate ability to destroy out-of-control cells. A vaccine can help tell the immune system what to do, to guide it toward finding and attacking cancer cells.

What have the clinical trials shown so far?

Funded by the Department of Defense, the phase I vaccine trial enrolled 16 adults who had been successfully treated for triple-negative breast cancer within the previous three years, but who were at high risk for the tumors coming back. The participants received three doses of the vaccine two weeks apart. After receiving the vaccine, they were monitored for side effects. Blood tests revealed how their immune systems responded.

The results were encouraging. Three-quarters of the patients developed immune responses that met the rigorous study threshold, with a measurable but lesser response noted in the remaining patients. Significant responses in key immune markers were seen 14 and 56 days after vaccination. No adverse side effects were observed, besides minor skin irritation at the injection site.

Could cancers someday become vaccine-preventable?

If it works, the triple-negative vaccine would not be the first to treat or prevent cancer. There is already a vaccine to prevent infection by several dangerous strains of human papillomavirus (HPV). Because those strains are responsible for most cervical cancers and many cancers of the throat and anus, the HPV vaccine indirectly but effectively prevents those cancers. In a similar way, vaccination against the hepatitis B virus can prevent liver cancer.

Cancer vaccines also exist to treat bladder cancers and advanced prostate cancer. But their success is often only modest. Treating preexisting tumors does not work nearly as well as preventing tumors from forming in the first place.

Developing vaccines to treat cancer is very difficult. For one thing, cancers arise from a person’s own cells, which the immune system may not easily recognize as harmful the way it does a virus from the outside world. Cancer cells can also suppress or escape the immune response. And cancers often arise in older people whose immune systems have weakened with age.

Tumors may grow too large for immune cells to fully reach and penetrate. That’s one reason the researchers at Cleveland Clinic and elsewhere are focused on vaccines that could prevent cancer outright or at least stop it very early.

“The immune system is very fickle,” Munster says. It can be hard to predict how it will respond to being stimulated. And if it overreacts, causing a massive inflammatory response and unwanted side effects, it can be hard to dial down, she notes. Dangerous and even lethal immune reactions to other types of immunotherapy have occurred.

“When you engage the immune system all of a sudden, you need to have a way to stop your response, and that’s not often trivial,” she says.

A future with cancer vaccines

Despite these challenges, around the world, studies are underway to test vaccines for bladder, blood, brain, cervical, colorectal, kidney, lung, skin, and pancreatic cancers. Other breast cancer vaccine trials have begun as well, most of them aimed at treating existing tumors or preventing tumors from recurring. Researchers are also working on vaccinations to prevent ovarian cancer and cancers of the lining of the uterus (also called endometrial cancer).

The Cleveland Clinic’s early vaccine trial targeting alpha-lactalbumin for triple-negative breast cancer was considered successful. Clinical trials will take several more years, and the vaccine’s success is not certain. But an effective, vaccine approved by the U.S. Food and Drug Administration (FDA) might allow many people at high risk to avoid having preemptive surgery on otherwise healthy breast tissue.

“Every day I see the needs of women who have triple-negative breast cancer, yet we don't currently have suitable advanced treatment options for them. Our ultimate goal is to offer a proactive approach to help women before they reach that point,” says G. Thomas Budd, MD, of Cleveland Clinic’s Taussig Cancer Institute. “Our hope for the future is to make available a vaccine that prevents triple-negative breast cancer in women at high genetic risk for this form of breast cancer who are otherwise healthy and cancer-free.”

“Any time you start on a new approach, it’s exciting,” Dr. Budd adds. “But also realize it’s going to take years to get to our final goal, and there are potential hurdles all along the way. I’m optimistic, though, that we can overcome those hurdles and help people who are at risk for breast cancer.”