Vaccine to Prevent Pancreatic Cancer Shows Early Promise

An off-the-shelf vaccine that targets common KRAS mutations appears safe and generates a durable immune response in people at a high risk for pancreatic cancer, according to a new phase 1 trial.

Researchers found that the experimental vaccine spurred KRAS-targeted immune responses in 18 of 20 trial participants, all of whom had a genetic predisposition to pancreatic ductal adenocarcinoma (PDAC) and evidence of pancreatic lesions.

After roughly 16 months of follow-up, none of the trial participants had developed cancer or high-risk lesions requiring surgery, and eight had partial or complete resolution of their pancreatic lesions.

Experts stressed that the findings, published online in Cancer Discovery, offer proof of concept that vaccinating against mutant KRAS can generate lasting immune responses.

It will take “many years” to show whether the strategy can prevent cancer, said study co-author Neeha Zaidi, MD, of Johns Hopkins University School of Medicine in Baltimore.

About 1 in 10 cases of PDAC are attributable to inherited genetic predisposition. Currently, people with such hereditary risk “can only ‘watch and wait’ with regular surveillance,” Zaidi noted.

“Options to proactively intercept disease progression are desperately needed,” she said.

A number of therapeutic vaccines for pancreatic cancer are under development, both personalized and off-the-shelf versions.

The vaccine used in the new trial, called mKRAS-VAX, targets six driver mutations in the KRAS gene that are present in about 90% of PDACs. The Hopkins team initially tested the vaccine as an adjuvant therapy, along with dual checkpoint blockade, in patients who’d undergone surgery for PDAC. In a phase 1 study published earlier this year, the vaccine elicited T-cell responses in nearly all of the 12 patients involved, and stronger T-cell response correlated with longer disease-free survival.

That prompted the researchers to investigate the vaccine’s preventive potential.

The new study is “a meaningful step” in that direction, said Alex Jaeger, PhD, molecular oncologist at Moffitt Cancer Center in Tampa, Florida, who was not involved in the work.

However, Jaeger told Medscape Medical News, many questions remain — most notably, can the strategy ultimately prevent cancer?

The trial included 20 people (median age, 66 years) with a hereditary predisposition to PDAC and radiographic evidence of ≥ 1 pancreatic lesion (typically a small cyst). Most had ≥ 1 first-degree relatives diagnosed with PDAC and harbored a germline mutation.

All participants received 4 subcutaneous doses of mKRAS-VAX given over 13 weeks. Eighteen (90%) were considered immune responders, showing an increase of at least 2.5 times in their pooled mutant KRAS-specific T-cell response.

T-cell responses rose by a median of > 18 times, and vaccine-induced mutant KRAS-specific T-cell clones were detectable for up to 2 years after vaccination. The responses were seen across a range of human leukocyte antigen alleles, which the researchers said supported their off-the-shelf approach.

The vaccine appeared to be generally safe. All treatment-related adverse events were grade 1 or 2, the most common being injection-site reactions (85%), self-limiting fatigue (70%), chills (40%), and flu-like symptoms (40%).

Zaidi said a follow-up trial is already underway. It will assess changes in precancer tissue to determine whether immune cells generated by the vaccine are not only detectable in the blood but also capable of infiltrating precancers.

They’re doing so, she noted, by vaccinating patients who need surgery for high-risk pancreatic cysts, which will allow them to collect both blood and tissue samples.

The study received funding from Stand Up to Cancer-Lustgarten Foundation, the National Institutes of Health, and the American Society of Clinical Oncology. Zaidi is cofounder of Adventris Pharmaceuticals, which has licensed a technology described in the study from Johns Hopkins University. Zaidi and the university are entitled to royalty distributions related to the technology. Jaeger reported having an equity stake in RyboDyn, a company developing immunotherapies.

A version of this article first appeared on Medscape.com.