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

摘要 胰腺癌是癌症相关死亡的主要原因，5年生存率低于5%， 目前的治疗方案包括化学-放射治疗。几乎所有胰腺癌患者 最终发展为转移性疾病，生存预后差。仍然有一个重要的机会 为改善胰腺癌患者的生活质量和预后的突破性策略。最近 研究表明质子治疗取得了一些成功，对质子RT的兴趣也在逐步增长 随着越来越多的证据表明相对于光子（XRT）的实质性益处。质子治疗的成功依赖于 - 在肿瘤组织中精确地递送高剂量，由于其布拉格峰的性质而保留正常组织， 同时保持与XRT相似的治疗优势。碳离子放射治疗（CIRT）提供了陡峭的 布拉格峰和更少的散射，但也更高的LET（线性能量转移），导致更大的电离事件 更大的生物伤害。我们假设更复杂的DNA损伤也被定义为相对的， CIRT的生物学效应（RBE）可诱导更强的免疫应答。在目前的提案中，我们正在测试 假设高LET CIRT单独应用时具有独特的增强肿瘤免疫应答的能力， 或与其它免疫抑制剂联合收割机。我们的目标是确定免疫调节的有效性 在胰腺癌小鼠模型中CIRT与XRT相比的差异。我们将测试高LET-CIRT对肿瘤的影响 细胞以及局部和全身水平的免疫细胞。我们将把生物学终点，如DNA 双链断裂（DSB），复杂的DNA损伤和XRT/CIRT照射细胞的克隆存活率， 它们根据目标1诱导免疫应答的能力。我们还将确定HDAC抑制是否能增强 胰腺肿瘤细胞的抗原呈递在AIM 2中。在目标3下，我们会采取以下措施， 使用检查点抑制剂的同时治疗重编程肿瘤微环境（TME），以及 抗原呈递活化剂。 本案无关这些研究的成功完成可以建立意义，并帮助我们设计独特的 用于实体瘤的免疫疗法与CIRT的组合疗法。

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.