IN IMMUNOTHERAPY, tumors can be considered hot or cold. “Hot” means there’s evidence of immune cells within the tumor, indicating immunotherapy treatments could enhance this initial response, while “cold” means the cancer doesn’t prompt an immune response, signaling immunotherapy likely would have little effect. Pancreatic cancer has long been considered a “cold tumor,” with scientists skeptical that vaccines could impact outcomes for this disease. New research, however, is starting to disprove that long-held belief.

During an April 7 session at the American Association for Cancer Research (AACR) Annual Meeting 2024 in San Diego, researchers presented findings on three vaccines that have safely stimulated immune responses in people with pancreatic cancer or at high risk of developing the disease. (The AACR publishes Cancer Today.)

Vaccine for People at High Risk for Pancreatic Cancer

Mutations in the KRAS gene occur in more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, according to Saurav Haldar, a medical oncology fellow at the Johns Hopkins Kimmel Cancer Center in Baltimore. He and colleagues hypothesized that a vaccine that causes the immune system to attack cells with these mutations could help prevent people at high risk for the disease from developing cancer.

“It can take more than a decade for pancreatic cancer to develop from the first precancerous cell,” Haldar said. “This therefore offers a large window of opportunity for intervention with immune-based interception strategies.”

In a phase I clinical trial, 15 people at high risk for developing PDAC received a vaccine designed to trigger a response against the six most common KRAS mutations. They then received follow-up doses at weeks three, five and 13. Researchers used blood samples to measure the presence of KRAS mutation-specific T cells at the start of the trial and at 17 weeks after vaccination.

All participants responded to the vaccine. Their volume of T cells multiplied a median of 12.3 times, with one participant’s immune cells increasing 167-fold. Twelve people produced T cells specific to all six KRAS mutations. “For the first time here, we demonstrate the induction of antigen-specific T-cell responses induced by an off-the-shelf mutant KRAS vaccine in a high-risk cohort of individuals with hereditary predisposition to developing pancreatic cancer,” Haldar said.

To date, none of the patients has developed pancreatic cancer, Haldar reported. One year after vaccination, three participants had follow-up blood tests, which showed the level of KRAS mutation-specific T cells had significantly decreased. Haldar said this suggests frequent boosters would be needed to maintain immunity.

Patients only reported mild side effects, such as injection site reactions, chills, fatigue and headache.

“This serves as a proof of concept to keep working on these types of strategies and hopefully bring them into the clinic in the future,” Haldar said.

Pre-surgery Vaccine for People with Pancreatic Cancer

Another off-the-shelf vaccine produced T-cell responses among people diagnosed with pancreatic cancer.

The vaccine GVAX, when administered before surgery, has been proven to trigger an immune response targeted at pancreatic cancer cells, according to Arielle Urman, a medical oncology fellow at the Johns Hopkins Kimmel Cancer Center and a study author.

In a phase I clinical trial, nine patients with stage I to III PDAC received standard-of-care chemotherapy—either with or without stereotactic body radiation therapy—followed by two cycles of GVAX, the immunotherapy drug Keytruda (pembrolizumab) and a CSF1R inhibitor. Participants then had surgery to remove their tumor, followed by optional chemotherapy and four more cycles of the vaccine, Keytruda and the CSF1R inhibitor. If patients then had no signs of disease, they received Keytruda every three weeks and GVAX every six months for a year.

The treatment produced a pathologic response in seven participants, with one experiencing a complete response, meaning they showed no evidence of cancer. The median disease-free survival was 12.6 months, while the median overall survival was 20.4 months. Among eight patients whose biopsies were analyzed, six displayed an 80% or higher increase in their immune cells.

Participants reported severe events in only two side effects, diarrhea and rash, along with mild injection site reactions and fever.

“The immunologic effect of triple therapy seen here warrants further exploration of combining vaccines with myeloid-targeting agents in pancreatic cancer,” Urman said.

Personalized Post-surgery Vaccine to Reduce Recurrence

A third vaccine uses technology popularized by COVID-19 vaccines to help prevent recurrence in people treated for pancreatic cancer.

Cancers produce neoantigens, which are proteins present in cancer cells but not in healthy cells, making them a prime target for cancer vaccines. With mRNA vaccines, the patient’s immune system is trained to recognize specific neoantigens as a threat. Researchers developed an mRNA vaccine individualized to the specific neoantigens expressed by each person’s tumor.

In a phase I clinical trial presented at the AACR Annual Meeting 2023 and published June 2023 in Nature,

16 people with PDAC underwent surgery to remove their cancer. This tumor tissue was sequenced to identify the neoantigens unique to each patient’s cancer, and vaccines that could recognize up to 20 neoantigens were created. Participants received the immune checkpoint inhibitor Tecentriq (atezolizumab), followed by eight weekly doses of the vaccine, 12 two-week cycles of chemotherapy and then a booster dose.

Half of the participants experienced increased levels of pancreatic cancer-specific T cells. “Early results indicated that vaccine immunity correlates with delayed recurrence,” said Vinod Balachandran, a surgical oncologist at Memorial Sloan Kettering Cancer Center in New York City and the trial’s principal investigator.

Balachandran presented three-year follow-up data, which found the eight patients who showed increased immune cell levels continued to have significantly longer recurrence-free survival than those with no response. Two of those who displayed immune activity had a recurrence, with one dying. These two participants had the fewest vaccine-induced T cells of the eight with a response.

Additionally, through blood analysis, researchers estimated lifespans for the immune cells generated by vaccination. They found the T cells had an estimated median lifespan of one year, but that jumped to six years with a booster dose. Approximately 20% of cells had an estimated lifespan of more than 10 years.

A phase II clinical trial that will compare using the vaccine, Tecentriq and chemotherapy with chemotherapy use alone is underway. “We now believe this is sufficient rationale to further broaden our efforts to test adjuvant neoantigen vaccines across a spectrum of cancer types,” Balachandran said.

Thomas Celona is an editor at Cancer Today.