Does vaccine-primed pancreatic cancer offer better candidates for immune-based therapies?

Abstract

Cancer immunotherapy is considered to be one of the biggest breakthroughs in cancer therapy in the last decade. However, the success of immunotherapy has so far been limited to a few solid malignancies including melanoma, renal cell carcinoma, non-small-cell lung cancer (NSCLC) and a few hematologic malignancies. In 2011, ipilimumab, a therapeutic monoclonal antibody that blocks CTLA-4, the bona fide immune checkpoint, was US FDA-approved for advanced melanoma [1]. Subsequently, other checkpoint inhibitors including anti-PD-1 and anti-PD-L1 blockade antibodies were also demonstrated to yield an objective response in approximately 20–30% of patients of these malignant diseases; and among the patients who had an objective response, many had a durable response [2–4]. One of anti-PD-1 antibodies (pembrolizumab) was most recently approved by US FDA for unresectable or metastatic melanoma. In addition, sipuleucel-T, a dendritic cell vaccine, has been shown to improve the overall survival of metastatic prostate cancer and subsequently gained FDA approval [5]. Nevertheless, significant objective response and durable responses were not seen in sipuleucel-T-treated pancreatic cancer patients. Melanoma, renal cell carcinoma and NSCLC were unique in their high infiltration of effector lymphocytes in tumor microenvironment (TME) [6]. By contrast, many other solid malignancies including pancreatic cancer are characterized by a highly immunosuppressive TME [7]. Immune tolerance mechanisms within the TME are a major obstacle to effective treatment of these cancers with immunotherapy. Pancreatic cancer and many other malignancies are thus considered ‘nonimmunogenic’ neoplasms. This notion has drastically slowed the development and application of immune-based therapies for these diseases.