Anticancer ELNP nanovaccines for curative treatmentof pancreatic cancer

The ultimate goal of this project is to develop innovative anticancer nanovaccines utilizing multifunctional ionizable lipid nanoparticles for the curative treatment of pancreatic ductal adenocarcinoma (PDAC). PDAC is recognized for its aggressive nature and notably poor long- term survival rates, presenting a pressing clinical need for effective curative therapies. While cancer immunotherapy has demonstrated the potential for disease-free outcomes, the efficacy of current clinical immunotherapies for PDAC is limited by the immunosuppressive tumor microenvironment. Our central hypothesis is that innovative nanosized therapeutic cancer vaccines, specifically targeting multiple mutant oncogenes in pancreatic ductal adenocarcinoma (PDAC), could potentially overcome tumor heterogeneity, thereby achieving a high rate of disease-free survival. Additionally, we believe that the synergistic combination of these nanovaccines with inhibitors targeting a potent immune checkpoint protein could markedly amplify antitumor immune responses and enhance overall therapeutic efficacy. To non- invasively assess the therapeutic impact of these nanovaccines, we will utilize cutting-edge magnetic resonance molecular imaging (MRMI) technology. This approach will not only facilitate the real-time evaluation of the nanovaccines' effectiveness but also guide the fine-tuning of both the nanovaccine formulation and the immunotherapy protocol. Towards this, we will 1) to design and develop multifunctional ionizable ELNP based peptide vaccine for effective immunotherapy of PDAC; 2) to determine therapeutic efficacy of the ELNP vaccines to treat PDAC in mouse models under MRMI guidance; 3) to explore the combination therapy of nanovaccine and VISTA blockade to improve the disease-free therapeutic outcomes. Multidisciplinary approaches will be applied to this project by a research team with complementary expertise in cancer biology, immunology, oncology, pathology, drug delivery, molecular imaging, and biomedical engineering from Case Western Reserve University and Cleveland Clinic. The successful completion of this project holds the promise of developing groundbreaking therapeutics tailored to meet the urgent clinical needs in the treatment of PDAC patients.