Research Project
10219980
ABSTRACT Pancreatic cancer is one of the most lethal cancers among all solid tumors, with an extremely poor prognosis, and a dismal five-year survival rate of 7%. New insights into the regulation of immune responses and the malignant process have led to the emergence of new immunotherapeutic strategies to treat pancreatic cancer. The challenges in the development of tumor vaccines lie in the identification of tumor-associated antigens, induction of antigen-specific cell mediated immune responses, overcoming immune tolerance, and the immunosuppressive tumor environment. In this U01 application, we propose to develop novel mucin-containing nanovaccine platforms and combine them with checkpoint blockade agents that can simultaneously induce long-lived cytotoxic T lymphocyte responses and activate innate immunity and maintain the T cell response, thus overcoming the immunosuppresive environment. Among the many structural and functional transformations that occur during oncogenesis, altered expression of cell surface glycoproteins, such as mucins, presents an opportunity for the development of vaccine strategies. We propose to utilize MUC4 mucin for immunotherapeutic nano-formulations because this protein is overexpressed in >90% of pancreatic tumors and undetectable in normal pancreas (unlike the most explored mucin vaccine candidate, MUC1). Our proposed nanoadjuvant platform consists of amphiphilic polyanhydride and/or polyester nanoparticles, containing CpG, and is ideally suited for protein-based subunit vaccines. Our central hypothesis, based on significant peer-reviewed preliminary data, is that a lead nanovaccine that induces MUC4-specific, cytotoxic CD8+ T cells will therapeutically (i.e., in the presence of tumor) provide anti-tumor benefits in combination with checkpoint inhibitors. We will position this nanovaccine for preclinical studies that will advance the development of pancreatic cancer vaccine technologies by accomplishing the following Specific Aims, each of which is bounded by milestones and fallback positions: Aim 1: Formulation, optimization, and immunological characterization of MUC4-specific immune responses with nano-adjuvants. Aim 2: Evaluation of lead nanovaccine(s) and checkpoint blockade agents in a syngeneic murine model of pancreatic cancer. Aim 3: Evaluation of lead nanovaccine and checkpoint blockade agents in transgenic mouse models. At the end of the project period, we will deliver a novel nanovaccine as an effective therapy for pancreatic cancer patients. Overall the proposed studies will establish the utility of MUC4, which is the most differentially overexpressed mucin as a target for pancreatic cancer immunotherapy, and the nanotechnology and cell and animal models generated in this project will have broader applicability for evaluating other pancreatic cancer vaccine approaches.
