For years, researchers have tested immune-based therapies in clinical trials to help the body recognize and fight cancer. In patients with metastatic disease, however, those immune responses often fade and building long-lasting protection has been difficult. 

Against this backdrop, a new analysis of a decades-old breast cancer trial points to a rare and unexpected finding: durable immune memory linked to long-term survival. 

More than 20 years after a small clinical trial tested a vaccine in women with advanced breast cancer, researchers at Duke Health revisited the participants to examine their immune systems. The work, led by Herbert Kim Lyerly, a physician and immunologist at the Duke University School of Medicine, focused on why the women’s outcomes appeared so unusual for metastatic disease. 

Researchers reported that the women still showed strong immune cells that could recognize their cancer. 

“We were stunned to see such durable immune responses so many years later,” Zachary Hartman, senior author of the study and an associate professor at the Duke University School of Medicine, said. “It made us ask: What if we could boost this response even more?” 

When the team analyzed the long-lasting immune cells that still recognized the women’s cancer, one signal stood out: Many carried CD27, a marker on certain immune cells that helps support long-term immune “memory,” or the ability to respond strongly again. 

The researchers stated that this pathway may help explain why the immune response persisted for years in this group. 

The study, published Jan. 30 in Science Immunology, framed CD27 as a potential target for strengthening therapeutic vaccine approaches.

To test that idea, researchers ran lab experiments in mice using a HER2-targeting vaccine. HER2 is a protein found at high levels on some breast cancer cells. 

Alongside, an antibody was designed to stimulate CD27. 

Nearly 40% of the mice treated with the combination had complete tumor regression, compared with 6% of mice given the vaccine alone. 

The team linked much of the effect to CD4-plus T cells. These are types of immune cells that help coordinate other immune responses. 

They are mainly treated as support cells, but in this case, they were central to building longer-term immune memory and strengthening anti-tumor activity. 

“This study really shifts our thinking,” Hartman said. “It shows that CD4-plus T cells aren’t just supporting actors; they can be powerful cancer fighters in their own right and are possibly essential for truly effective anti-tumor responses.” 

In follow-up experiments, the team reported that adding a separate antibody intended to further support CD8-plus T cells pushed tumor rejection rates in mice to nearly 90%. 

These cells are known for directly killing infected or cancerous cells. They also found the CD27-stimulating antibody did not require repeated dosing. 

In their models, a single dose given at the same time as the vaccine produced a lasting effect, a detail the researchers say could make the strategy easier to layer onto treatment plans that already involve multiple therapies. 

Hartman said the work helps explain why therapeutic vaccines have often struggled to deliver durable results on their own. 

“We’ve known for a long time that vaccines can work against cancer, but they haven’t lived up to the hype,” he said. “This could be a missing piece of the puzzle.” 

While the strongest results were seen in lab models, the findings point toward new ways to design immune-based treatments that may offer more durable protection for patients, an encouraging direction in a field where long-term responses have been difficult to achieve.