Immunotherapy and Prevention of Pancreatic Cancer

Pancreatic cancer remains a lethal tumor that is difficult to treat and, unfortunately, immune therapies that have garnered FDA approval in other tumors have shown little efficacy to date in this tumor. These therapies include checkpoint antibodies and engineered T cell infusions. A formidable problem in developing effective immunotherapy for PDA is the striking immunosuppressive and ‘immune-privileged’ tumor microenvironment. Few patients exhibit robust T cell infiltration in the tumor microenvironment, although when this does occur patient survival is prolonged. Major clinical efforts, justified by preclinical models, are now aimed at combination immune therapies that address multiple immune vulnerabilities in PDA in a nonredundant fashion. Generation of stronger adaptive immunity with vaccines and immune agonists may be necessary before antibodies against CTLA-4, PD-1, or PD-L1 will be effective. Pancreatic cancer is the third-leading cause of cancer mortality in the USA, recently surpassing breast cancer. A key component of pancreatic cancer’s lethality is its acquired immune privilege, which is driven by an immunosuppressive microenvironment, poor T cell infiltration, and a low mutational burden. Although immunotherapies such as checkpoint blockade or engineered T cells have yet to demonstrate efficacy, a growing body of evidence suggests that orthogonal combinations of these and other strategies could unlock immunotherapy in pancreatic cancer. In this Review article, we discuss promising immunotherapies currently under investigation in pancreatic cancer and provide a roadmap for the development of prevention vaccines for this and other cancers. Pancreatic cancer is the third-leading cause of cancer mortality in the USA, recently surpassing breast cancer. A key component of pancreatic cancer’s lethality is its acquired immune privilege, which is driven by an immunosuppressive microenvironment, poor T cell infiltration, and a low mutational burden. Although immunotherapies such as checkpoint blockade or engineered T cells have yet to demonstrate efficacy, a growing body of evidence suggests that orthogonal combinations of these and other strategies could unlock immunotherapy in pancreatic cancer. In this Review article, we discuss promising immunotherapies currently under investigation in pancreatic cancer and provide a roadmap for the development of prevention vaccines for this and other cancers.