Relative Immunological Effectiveness (RIE) of Carbon Ion Radiation Therapy for Pancreatic Cancer

Abstract Pancreatic cancer is the leading cause of cancer-related death with less than 5% (5-year) survival rate with current treatment regimen involving chemo-radiation therapy. Almost all patients with pancreatic cancer eventually develop metastatic disease with poor prognosis for survival. There remains a significant opportunity for breakthrough strategies to improve the quality of life and outcomes for pancreatic cancer patients. Recent studies have shown some success with proton therapy and the interest in proton RT has grown progressively with increasing evidence indicating substantial benefit over photons (XRT). The success of proton therapy relies on precise delivery of high dose in tumor tissue, sparing normal tissue due to the nature of its Bragg?s peak, while maintaining similar therapeutic advantages as XRT. Carbon ion radiation therapy (CIRT) offers steep Bragg?s peak and less scatter but also higher LET (Linear Energy Transfer), resulting in greater ionizing events and greater biological damage. We hypothesize that greater complex DNA damage also defined as relative biological effect (RBE) of CIRT can induce stronger immune response. In the current proposal, we are testing the hypothesis that high-LET CIRT has unique ability of enhancing tumor immune response, when applied alone or combine with other immunotherapeutic agents. Our goal is to determine the immunomodulation effectiveness of CIRT compared to XRT in pancreatic cancer mouse model. We will test the effect of high LET-CIRT on tumor cells as well as the immune cells at local and systemic level. We will correlate biological end points such as DNA double strand breaks (DSB), complex DNA damage and clonogenic survival in XRT/CIRT-irradiated cells with their ability to induce immune response under aim 1. We will also determine whether HDAC inhibition enhances antigen presentation by pancreatic tumor cells in aim 2. Under aim 3, we will enhance the efficacy of CIRT by reprogramming tumor microenvironment (TME) using concurrent treatment with check point inhibitors and antigen presentation activators. Relevance. Successful completion of these studies could establish the significance and help us design unique combination therapy of immunotherapy with CIRT for solid tumors.