A recent study published in Nature Communications, sponsored by the UCLA Health Jonsson Comprehensive Cancer Center, showed that adding immunotherapy to standard chemotherapy, before surgery, may benefit a subset of patients with borderline resectable pancreatic cancer. This clinical trial also used tumor tissue to investigate how the tumor environment responds to treatment. This allowed researchers to understand the trial results and generate new ideas feeding into future research. As senior author Dr. Timothy Donahue, Chief of the Division of Surgical Oncology and Professor of Surgery at the David Geffen School of Medicine at UCLA, put it, “Establishing this platform within the Agi Hirshberg Center for Pancreatic Diseases positions us to evaluate multiple new therapeutics in a systematic and translationally integrated way in the future”.
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, remains a devastating diagnosis for almost all patients due to advanced disease at time of diagnosis and limited treatment options. Surgery to remove the tumor can be curative but very few patients present with localized disease that qualify them for resection. A more recent advancement for advanced PDAC has been the adoption of a four-drug combination chemotherapy called FOLFIRINOX. This potent cocktail combines leucovorin, irinotecan, fluorouracil, and oxaliplatin and has increased survival for patients with advanced disease. For patients with tumors that are localized but sit near major blood vessels surgery is riskier and more complex. These patients are often treated first with chemotherapy to increase their chances for surgical resection, improving their long-term prognoses. In other types of cancer, such as lung cancer, adding immunotherapy to chemotherapy has allowed more patients to undergo surgery. Immunotherapy increases the activity of the patient’s immune system to fight their cancer. For PDAC, there hasn’t been an evaluation of FOLFIRINOX combined with immunotherapy in the pre-surgical setting.
In this study, patients with borderline resectable PDAC were treated with a combination of FOLFIRINOX and nivolumab (an immunotherapy agent) prior to surgery to remove their tumors. Additionally, tumor tissue was evaluated after resection to understand the cellular changes caused by the immunotherapy and relate them to surgical outcomes. To evaluate the tumor tissue, researchers used several techniques that allowed them to evaluate gene and protein expression by cells and understand where different cell types (tumor cells vs immune cells) were located in the tumor (spatial transcriptomics).
The team found that the addition of immunotherapy to FOLFIRINOX was safe, causing no additional side effects and no immune adverse events. While the percentage of patients able to receive surgery after the combo was increased, the overall effect of the addition of immunotherapy to chemotherapy was similar to earlier studies of FOLFIRINOX alone. However, there was a small number of patients who had exemplary and durable results; 2 patients who achieved complete disappearance of cancer and 2 patients who had a near complete disappearance of detectable cancer. Understanding why these four patients had such a strong response can help identify biomarkers for people who will respond to this treatment combination or similar immunotherapy approaches. Jason Link, PhD and associate professor of surgery at the David Geffen School of Medicine at UCLA, is a Catalyst Grant awardee whose work is focused on these rare patients demonstrate that, under certain conditions, the immune system can keep pancreatic cancer in check.
By analyzing tumor tissue after treatment and comparing it to pre-treatment biopsies, researchers were able to catalog changes caused by the combination of immunotherapy and FOLFIRINOX. This study found that in tumors treated with a combination of nivolumab and FOLFIRINOX there were disorganized clusters of immune cells present within the tumor. These clusters included antibody-secreting plasma cells and “exhausted” CD8+ T cells that have the capacity to recognize and kill tumor cells but are dysfunctional. These observations suggest that any immune system activation was ultimately suppressed and helps to explain the lack of additional clinical benefit to the immunotherapy and chemotherapy combination. They also allow researchers to understand how immune cells changes in pancreatic cancer differ from cancers that do respond to immunotherapy.
“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 response,” said Dr. Donahue in a UCLA Health article.
Immunotherapy has transformed outcomes in many cancers, but pancreatic cancer remains resistant. Studies like this are critical to understanding how to use immunotherapy to improve patient outcomes and identify sub-sets of patients that could benefit from immune-based treatments. By pairing clinical trials with in-depth translational study of the tumor’s cellular and molecular landscape, researchers are creating a roadmap for more precise, patient-specific treatments and developing next-generation therapies designed to overcome pancreatic cancer’s unique biology.
