Neoadjuvant Immunotherapy for Localized Pancreatic Cancer: Challenges and Early Results

SIMPLE SUMMARY: Pancreatic cancer is a deadly disease with limited effective treatments. Despite growing interest in immunotherapy for other cancer types, immunotherapy has not shown significant utility in metastatic pancreatic cancer. However, investigators are examining the role of immunotherapy in the preoperative setting in order to prime the immune system to detect and prevent micrometastatic disease and recurrence. This scoping review describes 9 published trials of preoperative immunotherapy and summarizes 27 ongoing trials using preoperative immunotherapy, generally in combination with other standard neoadjuvant therapy. The results of these early trials have been promising but have not conclusively established a role for preoperative immunotherapy in pancreatic cancer. The results of the ongoing trials may be able to demonstrate whether combination immunotherapy prior to surgery can improve long-term outcomes. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease due to its late presentation and tendency to recur early even after optimal surgical resection. Currently, there are limited options for effective systemic therapy. In addition, PDAC typically generates an immune-suppressive tumor microenvironment; trials of immunotherapy in metastatic PDAC have yielded disappointing results. There is considerable interest in using immunotherapy approaches in the neoadjuvant setting in order to prime the immune system to detect and prevent micrometastatic disease and recurrence. A scoping review was conducted to identify published and ongoing trials utilizing preoperative immunotherapy. In total, 9 published trials and 27 ongoing trials were identified. The published trials included neoadjuvant immune checkpoint inhibitors, cancer vaccines, and other immune-modulating agents that target mechanisms distinct from that of immune checkpoint inhibition. Most of these are early phase trials which suggest improvements in disease-free and overall survival when combined with standard neoadjuvant therapy. Ongoing trials are exploring various combinations of these agents with each other and with chemotherapy and/or radiation. Rational combination immunotherapy in addition to standard neoadjuvant therapy has the potential to improve outcomes in PDAC, but further clinical trials are needed, particularly those which utilize an adaptive trial design.