Project Summary FLASH radiotherapy is an exciting potentially transformative innovation in radiation therapy with potential to ablate tumors at ultra-high dose rates without significantly damaging nearby normal tissues. FLASH radiotherapy could become the optimal or perfect radiotherapy approach for treating pancreatic cancer at ablative biologically effective doses of over 100 Gy, by overcoming the current dose-limits of neighboring normal organs, specifically stomach and bowel. Recent studies have also indicated that FLASH radiotherapy can make the tumor microenvironment more immunogenic. Hence, radio-immunotherapy combining FLASH radiotherapy and immunotherapy to cause regression of both locally irradiated and distantly unirradiated/metastatic tumors would be an excellent option for treating pancreatic cancer. In this project we propose the development of a PERFECT (Proton Enhanced Radio-immunotherapy with FLASH Effect in Cancer Treatment) approach for pancreatic cancer, integrating the use of smart radiotherapy biomaterials (SRBs) to sustainably deliver synergistic immunotherapy. The overall hypothesis for this project is that the PERFECT approach for pancreatic cancer will significantly increase survival and quality of life with minimal toxicities or side effects. The project milestones include publishing optimal parameters for maximizing effectiveness of the PERFECT approach and publishing comprehensive safety and pharmacokinetics data needed for clinical translation. The highest significance of this approach is anticipated in significantly increasing survival and quality of life for pancreatic cancer, where current survival options are limited and prognosis is poor. The approach is also expected to significantly reduce treatment time and costs, with potential to reduce disparities in access to treatment. The project will involve collaborations between faculty at Howard University and neighboring Johns Hopkins with complementary expertise for carrying out the project and mentorship/research education of trainees from both institutions.