Facts and Hopes in Immunotherapy of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancers to treat. For patients with advanced and metastatic disease, chemotherapy has yielded only modest incre-mental benefits, which are not durable. Immunotherapy has revolutionized the treatment of other solid tumors by leading to cures where none existed only a decade ago, yet it has made few inroads with PDAC. A host of trials with promising pre -clinical data have failed, except for in a small minority of patients with selected biomarkers. There is, however, a glimmer of hope, which we seek to cultivate. In this review, we discuss recent advances in the understanding of the uniquely immunosuppres-sive tumor microenvironment (TME) in PDAC, learnings from completed trials of checkpoint inhibitors, TME modifiers, cellu-lar and vaccine therapies, oncolytic viruses, and other novel approaches. We go on to discuss our expectations for improved preclinical models of immunotherapy in PDAC, new approaches to modifying the TME including the myeloid compartment, and emerging biomarkers to better select patients who may benefit from immunotherapy. We also discuss improvements in clinical trial design specific to immunotherapy that will help us better measure success when we find it. Finally, we discuss the urgent imperative to better design and execute bold, but rational, combination trials of novel agents designed to cure patients with PDAC.