Pancreatic cancer remains a major clinical challenge claiming more than 40,000 lives yearly in the US. Despite many advances in understanding the biology of pancreatic cancer, the disease still imposes challenges in its early detection and effective therapy. Pancreatic Ductal Adenocarcinoma (PDAC) is the most common type and accounts for 95% of cases of pancreatic cancers. Many risk factors including chronic inflammation, diabetes, obesity, and smoking have been established. PDAC is highly resistant to chemotherapy and radiation. The only curative intervention is surgery for localized disease; however, most patients present with locally-advanced disease and are not eligible for curative surgical approaches. The overall 5-year survival is 5%.
After decades of research, new immunotherapy approaches have resulted in unprecedentedly positive results in a subset of many types of tumors including, but not limited to lymphoma, melanoma, renal cell carcinoma, and lung adenocarcinoma. In particular, checkpoint inhibitors have produced long-term survival in approximately 20% of patients, and these findings led to FDA approval of several agents (ipilimumab, nivolumab, pembrolizumab). Cellular therapies with genetically engineered T cells (CAR-T-cells or antigen-specific T cell receptors) or tumor infiltrating lymphocytes (TILs) have also proven to be efficacious in certain hematopoietic malignancies and solid tumors. Therapeutic vaccines have shown some success as well. Immunotherapy, in many cases, provides an alternative to traditional chemotherapy, and often with less severe side effects. The search for reliable predictive markers for immunotherapy is ongoing.
Immunotherapeutic approaches to PDAC, however, have not, for the most part, been successful. PDAC has a low mutational load with few neoantigens (an immunologically “quiet” tumor); although inflammatory cells have been shown to infiltrate the tumor, these cells promote rather than inhibit PDAC growth. The tumor microenvironment is profoundly immunosuppressive with regulatory T cells, regulatory B cells, myeloid-derived suppressor cells, tumor associated macrophages, and other stromal elements that interact with the tumor and/or secrete suppressive factors. Despite the number of cells that surround and infiltrate the tumor, only a minority of these tumors have naturally occurring effector T cells. However, several groups have recently reported techniques that overcome the immunosuppressive milieu of PDAC and allow the host immune system to react more efficiently against the tumor.
The readiness of the scientific community to pursue these types of studies underscores the need for projects that would move discoveries into early phase clinical trials. The proposed work will allow the most advanced scientific and clinical teams to perform their work in a more coordinated way with access to common resources and with the option to conduct early clinical trials, particularly with agents developed at the grantee institution or in collaboration with industry.