Immunotherapy Plus Chemotherapy Before Surgery Shows Promise for Pancreatic Cancer

A UCLA investigator-initiated clinical trial has found that adding immunotherapy to standard chemotherapy before surgery is safe and shows promise for some patients with borderline-resectable pancreatic cancer, a disease that has historically been difficult to treat. The findings, published in Nature Communications, show that while the combination did not produce a clear survival advantage for most patients, a notable subset experienced unusually deep and durable responses.

Researchers conducted a single-arm Phase 1b/2 clinical trial in 28 patients with borderline-resectable pancreatic cancer. Patients received modified FOLFIRINOX chemotherapy combined with the immunotherapy drug nivolumab before surgery. This approach allowed investigators to directly analyze tumor tissue removed during surgery and compare it with pretreatment biopsies and historical samples from patients who received chemotherapy alone. The team used advanced techniques, including gene expression analysis, immunohistochemistry and spatial transcriptomics, to examine how the treatment altered the tumor's immune landscape.

Most patients tolerated the combination treatment well and were able to proceed to surgery, with no serious immune-related side effects or treatment-related delays. 79% of patients went on to surgical resection, and all patients who underwent surgery had their tumors successfully removed. 86% had clean margins, and 50% had no cancer detected in their lymph nodes.

While overall survival outcomes were similar to those typically achieved with chemotherapy alone, a subset of patients experienced unusually strong and durable responses. 9% had complete disappearance of detectable cancer at the time of surgery, and another 9% had near-complete responses.

Immune analyses showed that immunotherapy increased immune activity within tumors, including higher levels of cancer-killing CD8 T cells. At the same time, treatment was associated with changes in the tumor immune environment marked by disorganized immune cell clusters and an accumulation of plasma cells and exhausted T cells, which are immune cells that are activated but less effective at attacking cancer. These findings may help explain why immunotherapy often triggers immune activation without translating into long-term tumor control in pancreatic cancer and point to strategies for improving future combination therapies.

Pancreatic cancer remains one of the deadliest cancers, with few effective treatment options and limited benefit from immunotherapy, which has transformed care for many other cancer types. In diseases such as lung and breast cancer, giving immunotherapy alongside chemotherapy before surgery has significantly improved outcomes, but this strategy has rarely been tested in pancreatic cancer. By focusing on patients with borderline-resectable disease, a group for whom surgery is possible but technically challenging, this study provides an opportunity to evaluate whether immunotherapy can improve surgical success and survival, while also revealing how the tumor's immune environment responds.

The study provides important insight into why immune-based treatments have shown limited success in pancreatic cancer, revealing that while immunotherapy activates immune cells within tumors, it may also disrupt immune organization and promote immune exhaustion. Future research will focus on identifying patients most likely to benefit and developing strategies that better support effective, sustained anti-tumor immune responses.

"By testing this novel drug combination in the preoperative setting, we were able to directly compare pre-treatment biopsies with surgical resection specimens to better understand why the therapy works in some patients, and, just as importantly, why it does not in others, and what additional strategies might improve responses," said the chief of surgical oncology at the David Geffen School of Medicine at UCLA.