Taking a Shot Against Cancer Recurrences

IN FEBRUARY 2018, 41-year-old Jennifer Davis from Lisbon, Ohio, felt a lump in her left breast. She tried not to think the worst, reminding herself that she was young and had no family history of breast cancer. And while a mammogram showed a suspicious spot, a follow-up biopsy came back negative for cancer. By September 2018, though, the lump had grown larger, and her physician ordered another biopsy. This time, the mother of three got devastating news: She had triple-negative breast cancer (TNBC).

“Triple-negative” means her cancer lacked receptors for estrogen or progesterone hormones, and had little or none of a protein called HER2. TNBC—which accounts for 10% to 15% of all breast cancers—is more common in women diagnosed before age 40, Black women and women who have a BRCA1 mutation. TNBC also tends to grow and spread faster and has fewer treatment options than other types of breast cancer. While Davis’ cancer appeared isolated to her breast alone, earlier-stage TNBC is known to return after treatment in about 40% of cases.

In October 2018, Davis started on chemotherapy—four rounds of Adriamycin (doxorubicin) followed by seven rounds of Taxol (paclitaxel). In March 2019, she had surgery to remove both breasts and was told afterward there were no signs of cancer. Despite that, she faced 26 rounds of radiation to reduce the risk of cancer recurrence. For the next two years after radiation therapy, Davis received scans every three months to monitor for recurrence, but she couldn’t shake her fear that the cancer would return. “I was just worried every single day,” she says.

Her mindset shifted when her oncologists at the Cleveland Clinic suggested she consider enrolling in a phase I clinical trial testing an experimental vaccine for women with a history of TNBC and high risk for recurrence. A phase I trial includes a small number of people and is intended to test a drug’s safety and establish the maximum tolerable dose. The vaccine, which was developed at the Cleveland Clinic, targets a protein called alpha-lactalbumin, which is highly expressed in most cases of TNBC, to generate an immune response with the promise of fighting against cancer.

The protein-based vaccine hadn’t been tested in people before, but Davis was encouraged by data showing it had produced an immune response that helped keep TNBC tumors from growing in mice. Without hesitation, she enrolled in the trial and received three doses of the alpha-lactalbumin vaccine every two weeks, receiving the final one in November 2021.

“I was desperate to try and do anything,” Davis says. “[The experimental vaccine] wasn’t a fear for me. … I felt more just excitement and peace of mind.”

Cancer Vaccine Development

Traditional vaccines build immunity against diseases such as measles or the flu, which are caused by viral infections. In general, these vaccines use inactive viruses or parts of viruses that do not infect the recipient to train the immune system to recognize and remember infectious agents that cause diseases. In the same way, human papillomavirus (HPV) and hepatitis B vaccines help prevent cervical and some liver cancers, respectively, by using part of the surface protein from viruses that drive those cancer types.

In addition, the Food and Drug Administration has also approved a handful of therapeutic cancer vaccines, which are administered as part of treatment rather than to prevent cancers. Some of these vaccines treat early-stage bladder cancer, metastatic prostate cancer and advanced melanoma.

The alpha-lactalbumin proteins that Davis received via the vaccine are normally only expressed in lactating breast tissue after a pregnancy. The absence of this protein in most breast tissue and its high expression in TNBC make it a promising target for training the immune system to recognize and respond to the cancer.

Some earlier attempts to develop cancer vaccines haven’t worked well because they targeted proteins also found in healthy tissue, says Neeha Zaidi, a cancer vaccine researcher and medical oncologist specializing in pancreatic and colorectal cancers at Johns Hopkins Medicine in Baltimore. “The main thing that’s different now is the fact that we have new technologies to push things forward,” Zaidi says.

Advances in rapid and lower-cost DNA sequencing technology now make it feasible for researchers to identify unique proteins that appear only in cancer cells, she explains. These cancer-specific proteins, known as neoantigens, accumulate as cancer cells divide and pick up new mutations. Once identified, neoantigens can be used as highly specific vaccine targets. In addition, the development and recent success of mRNA vaccine technology—brought to the fore by the COVID-19 pandemic—allows researchers to introduce a piece of mRNA that spurs human cells to produce a protein. In the case of COVID-19 vaccines, this is called a spike protein, which is also present on the virus’ surface. For cancer, mRNA vaccines encoding neoantigens can make cells produce portions of cancer-specific proteins quickly and inexpensively—so the immune system can recognize the cancer.

Several developments have helped to advance cancer vaccines, including vaccines for breast and ovarian cancers, says Mary “Nora” Disis, an oncologist and expert in immunotherapy at the University of Washington and Fred Hutchinson Cancer Center in Seattle. The first, she explains, is understanding that a successful vaccine needs to generate T cells that can “actually destroy” cancer tissue. Researchers now recognize that many proteins, such as HER2 in breast cancer, turn up at high levels in other types of cancer. These proteins could be useful in developing vaccines that generate effective immune responses against multiple cancer types.

Disis sees cancer vaccines making the most initial headway in preventing cancer recurrence in those who have already been treated for the disease. “I would say, we’re probably going to see a vaccine approved to prevent disease recurrence [in one or more cancer types] within the next five to eight years, [and that’s] only because it will take that long to run the clinical trials,” she says.

Early Trial Results

Disis and her team discovered that certain portions of the HER2 protein, which can cause uncontrolled cancer growth, rev up the immune system. Their research has focused on delivering a vaccine that includes the portion of DNA that encodes those bits of the protein.

In a study published January 2023 in JAMA Oncology, Disis and colleagues reported results of a phase I clinical trial testing the vaccine in 66 patients with stage III or IV HER2-positive breast cancer. Participants had completed standard therapy and had either no evidence of disease or had cancer that was only present in the bones. They received three doses of the vaccine over the course of three months. The study found the vaccine to be safe, with participants reporting side effects such as aches and fatigue. They also found the vaccine elicited sustained immune responses, including an increase in memory T cells in blood that are known to be important for lasting immunity. After 10 years, about 75% of all those who received the vaccine were still living. (About 85% of the patients in study arm II, who received the intermediate dose, were still alive.)

Recently reported results of a phase II trial testing an mRNA-based neoantigen vaccine developed against melanoma, delivered in combination with the immune checkpoint inhibitor Keytruda (pembrolizumab), are also encouraging. The personalized vaccine is custom made for each individual’s cancer. It encodes up to 34 neoantigens from a person’s melanoma cancer cells and uses other agents that can amplify an immune response. All 157 participants in the study had surgery to remove high-risk stage III or IV melanoma followed by the immunotherapy, but 107 patients also received nine doses of the vaccine.

An analysis at 18 months showed a 44% reduction in the risk of recurrence or death in those who received the vaccine compared with those who received Keytruda alone. In the combination treatment arm, 78.6% were recurrence-free at 18 months compared with 62.2% in the Keytruda-only arm. In December 2023, manufacturers of the vaccines announced that the combination continued to show benefit after three years, cutting the risk of recurrence or death nearly in half compared with immunotherapy alone. A larger phase III trial is underway and is expected to enroll patients with melanoma through 2024.

“At the end of the study, I hope we’ll have a winner,” says Jeffrey Weber, deputy director of the Perlmutter Cancer Center in New York City and the principal investigator of the trial. “We’ll know by the end of 2025, and that’ll be a real game-changer. The side effects are minor, similar to a COVID shot.” While it’s not yet clear if the vaccine will be effective when the cancer has metastasized, Weber considers it a “major advance” for people whose melanoma can be surgically removed.

In addition, in a study published in the June 1, 2023, issue of Nature, researchers described a personalized mRNA-based neoantigen vaccine. This vaccine was used along with an immune checkpoint inhibitor in 16 patients after they had surgery for pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer; 15 of these patients also received chemotherapy. Eight of the 16 patients generated substantial T-cell responses targeting one or more of the neoantigens specific to their tumors. After 18 months, the people who had these vaccine-generated T cells had a longer recurrence-free survival than those who did not show a T-cell response, suggesting the combination of the vaccine and other treatments could activate the immune system to hold off cancer recurrence.

The findings are noteworthy in part because the five-year relative survival rate for pancreatic cancer is 12.5%. In addition, this type of cancer doesn’t typically respond to immunotherapy alone since it doesn’t carry many mutations. This means there are fewer cancer-specific proteins to target compared with other cancers, like melanoma, which are more likely to respond to immunotherapy. Zaidi is part of a Johns Hopkins team now working to develop vaccines that leverage the protein known as K-Ras that is expressed in up to 90% of pancreatic cancers. K-Ras proteins and associated genes are expressed early in pancreatic cancer development, raising the possibility that a vaccine might one day fight pancreatic tumors in a precancerous phase in people who are known to be at higher risk, Zaidi says.

Hope for the Future

In December 2023, the biotechnology company Anixa Biosciences, which develops therapies and vaccines for hard-to-treat cancers, announced findings on the alpha-lactalbumin vaccine that Davis was given in 2021. These findings showed that most patients developed immune responses that appear promising for fighting cancer—but only time will tell if they reduce recurrences. The only significant side effect noted was irritation at the injection site. Parallel study arms of the trial are exploring use of the vaccine with Keytruda and in people who do not yet have TNBC but are at high risk of developing it.

“We’re very careful not to overpromise,” says Justin Johnson, the research laboratory program manager at the Cleveland Clinic Lerner Research Institute. “We don’t want to jump to conclusions and say because there is an immune response that this will confer protection [against TNBC recurrence] or get through phase II [clinical trials], but we’re hopeful.”

Davis says that before she received the vaccine, she was often preoccupied with thoughts that she would miss major events in her children’s lives. The promise of the vaccine she received and the immune cells circulating in her body helped set her mind at ease.

“Now I live for the moment,” Davis says. “It’s been the biggest blessing to think about where it might go in the future.”