The goal of this application is to apply our vault nanocapsule platform for the development of a survivin- vault therapeutic vaccine to treat pancreatic cancer. For the past 40 years, there have been no notable improvements to patient survival. In 2018, it is estimated that 55,440 people will be diagnosed with pancreatic cancer and 44,330 will die from the disease, in the US alone. Treatment with a therapeutic cancer vaccine stimulates the patient?s immune system to develop a specific anti-tumor response and is a promising strategy for cancer immunotherapy. Safe and effective delivery of the vaccine is necessary for successful treatment. Delivery vehicles, including liposomes, virus-like particles and bacterial vectors, have been employed; however, immunogenicity of these vehicles prevent booster dosing which is necessary to achieve a sustained anti-tumor response. Cell-based therapies overcome the inadequacy of most delivery vehicles, but manufacturing is expensive, time-consuming and inefficient. Vault nanocapsules are unique, natural hollow protein shells that are biodegradable, biocompatible, non-toxic and non-immunogenic. Found in the cytoplasm of most eukaryotic cells, vaults may naturally function to bring antigens for presentation. Survivin is a tumor associated antigen broadly expressed by tumors, including pancreatic ductal adenocarcinoma. The vault nanocapsule is the only true natural human nanoparticle and the only nanocapsule that has the potential to deliver antigens through a natural pathway. Our proprietary and patent-pending technologies for the vault nanocapsule platform will make the survivin-vault nanovaccine a safe and effective cancer treatment for pancreatic cancer. In this proposal, we will: 1) produce vault nanocapsules that encapsulate survivin, 2) assess the magnitude and potency of the immune response following immunization with the survivin-vault nanovaccine, and 3) characterize the therapeutic anti-tumor immune response stimulated by the survivin-vault vaccine in an orthotopic KrasG12D, Trp53R172H, PDX-1-Cre (KPC) murine model of pancreatic cancer. In the Phase II STTR, the efficacy of our survivin-vault nanovaccine will be further validated using an autochthonous KPC tumor model for advanced metastatic pancreatic cancer and the production will be converted to comply with current good manufacturing practice (cGMP) regulations, thus enabling preparation of an IND application for clinical testing.
Pancreatic cancer is a deadly disease that has a dismal 5-year survival rate of 8%. To overcome the immunosuppressive tumor microenvironment and poor tumor antigenicity, we propose using the vault nanocapsule for the delivery of a therapeutic cancer vaccine that targets survivin, a tumor associated antigen predominantly expressed in cancer cells. Our vault nanocapsule platform has the potential to stimulate an effective survivin-specific T-cell response that will promote a sustained protective anti-tumor immunity and lead to prolonged patient survival.