While immunotherapy has dramatically improved treatment for some cancers, it has not had the same results for pancreatic cancer patients.

Researchers are trying to learn more about why immunotherapeutic treatments do not work for pancreatic cancer. As part of this effort, a group of researchers took a closer look at patients who benefitted from this treatment. “Exceptional responders to immunotherapy in pancreatic cancer: A multi-institutional case series of a rare occurrence” was published in June 2025, in the journal Oncotarget. The report focuses on cases where it DID help some patients, extending longer-term survival beyond historical norms. “These cases are rare, but there are probably many more examples out there than what we found for this study,” says surgeon–scientist Jordan Winter, M.D., one of the study leaders.

When Immunotherapy Works

Research shows there are several reasons why immunotherapy has not yet shown significant efficacy in pancreatic cancer treatment. Among them is the immunosuppressive tumor microenvironment characterized by a dense, fibrotic stroma that acts as a physical barrier, preventing immune cells like T cells from reaching the tumor cells. Pancreatic tumors also contain numerous immunosuppressive cells, such as tumor-associated macrophages and myeloid-derived suppressor cells that actively inhibit immune responses.

Yet, these patients responded to immunotherapy treatment. “What that tells us is that there is something about these patients that’s unique,” says Winter, director, surgical services, at UH Seidman Cancer Center in Cleveland, Ohio. Winter also holds the John and Peggy Garson Family Endowed Chair in Pancreatic Cancer Research and Jerome A. and Joy Weinberger Family Master Clinician in Surgical Oncology. “An important way to learn how to improve therapies is to study the outliers, and now we know that there are very real outliers with pancreatic cancer who respond to immunotherapy,” he explains. “We really need to look at these exceptional responders more in depth.”

About the Study

The researchers examined medical records from 14 patients with pancreatic ductal adenocarcinoma who had unexpectedly positive responses to immunotherapies. These immunotherapies included different types of immune checkpoint inhibitors such as pembrolizumab, nivolumab, and ipilimumab, and agents targeting tumor-associated macrophages. To find these exceptional responders, 471 oncologists from 91 major U.S. cancer centers were contacted.

The bulk of patients in this study had advanced or metastatic disease and had already progressed after standard treatments. These patients received immunotherapy alone and were selected for inclusion due to a reduction in tumor size on imaging or a drop in the blood marker CA 19-9. “If we wanted to see the effects of immunotherapy alone, we absolutely had to exclude patients who were receiving combinational treatments,” Winter notes, adding that he was not all that surprised about finding individuals who would respond to immunotherapy.

“About 10 years ago I had a patient with very advanced pancreatic cancer whose life expectancy was less than a few months, maybe weeks,” he relates. The patient opted to try immunotherapy. “This patient had two treatments and he wound up living another year,” he continues. “He was the catalyst that got me thinking there have to be other people like him. And we need to find them and then we need to find out why they responded so well.”

Indeed, the results of the study showed that median progression- free survival was 12 months, and most patients were still alive at follow-up, with survival rates of 80 percent at one year and 70 percent at two years.

What was particularly intriguing to the researchers was more than half of the patients selected did not have high microsatellite instability (MSI-high), a known, but very rare, biomarker for potentially more successful immunotherapy treatment in pancreatic cancer. “The majority of patients we see are not MSI- high, just like in this study,” Winter says. “So there has to be some other biological mechanism going on with these patientsthat made immunotherapy work for them.”

This case series is the largest to date focused exclusively on exceptional immunotherapy responders in pancreatic cancer. “What we’re showing is that there’s a real need to expand biomarker research and molecular profiling in this disease so we can personalize treatment,” Winter explains. “That’s how we can then potentially develop a strategy to make immunotherapy more effective.”