Current advances in immunotherapy for pancreatic cancer

Outside of treatments for melanoma and renal cell, immunotherapy for solid tumors has been a major challenge. However, more recent data with agents targeting negative regulatory molecules on activated T cells, such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1), are showing promise not only in the traditionally more immunogenic tumors such as melanoma and renal cell carcinoma but are also showing glimpses of activity in non–small cell lung cancer, as well as anecdotal cases of responses in colorectal cancer, and gastric cancer. Identification of predictive biomarkers would increase the therapeutic yield of these agents across all disease types. A complementary area of immunotherapy research is that of therapeutic cancer vaccines. Cancer vaccines are not vaccines in the traditional sense in that they aim to treat and not prevent established disease. The most notable success is that of sipuleucel-T, an autologous cellular product immunotherapy, which has shown a survival benefit in the treatment of metastatic castration-resistant prostate cancer. Despite successes in other cancers, immunotherapy in pancreatic ductal adenocarcinoma (PDA) remains difficult. However, there are recent signals of activity that suggest there is potential for success. Lessons learned from successes and failures can be used to move immunotherapy forward in PDA. Furthermore, knowledge from preclinical testing in more immune-tolerant models must be integrated into clinical testing. Unlike melanoma, PDA does not have many tumor-infiltrating lymphocytes at baseline to be activated by immune stimulants. Successful immunotherapy strategies most often involve vaccines that efficiently deliver antigen to an antigen-presenting cell (APC) in the context of costimulatory signals or combination strategies that induce tumor-specific T cells and promote their activity by adding agents that either provide costimulation or block negative regulatory signaling. Although preclinical modeling does not always predict success in patients, they can serve as a guide as to what is more likely to work, and data suggest the need for vaccines and combinations that are more potent. This review focuses on recent completed immunotherapy trials in PDAs and the lessons learned from both failures and successes that may help guide future development in this very exciting field, with the hopes of bringing this treatment modality to patients with PDA.