Effects of FLASH Radiation on Cancer and the Immune Response

项目概要/摘要 背景：放射治疗（RT）是一种核心治疗方式，可使多种类型的肿瘤患者受益。 癌症，并且可以与免疫检查点阻断疗法协同作用。然而，提供最有效的 对肿瘤的辐射剂量受到对正常组织的附带损害的限制。我们正在开发下一个- 新一代临床RT平台PHASER将提供超快速和精确的辐射（FLASH）， 显著减少对正常组织的损伤。使用我们开发的独特的临床前FLASH辐照器， 我们的初步数据显示，与常规剂量率照射相比， 以及免疫细胞向肿瘤中的浸润增加，提示免疫介导的机制。 假设和目的：我们假设FLASH将通过以下方式显示出上级的治疗指数： 与用于多种癌症的常规剂量率RT相比，不仅基于其精度，而且基于 诱导更有效抗肿瘤免疫。我们将在癌症实验模型中检验这一假设。 具体目的和研究设计：目的1：比较抗肿瘤效力、安全性和免疫学 FLASH与常规剂量率RT在原发性肿瘤中的作用：我们将评估不同剂量的 FLASH和比较其效果与最大耐受剂量的常规剂量率RT在两个同基因 和患者来源的异种移植小鼠模型。除了评估肿瘤生长，我们还将分析 FLASH对免疫反应的影响，通过使用CyTOF和我们的 SCAFFOLDS算法。这种方法将揭示在哪里以及哪些免疫细胞亚群被激活， 成功治疗的动物我们还将评估FLASH毒性降低的免疫学相关性。 目的2：分析FLASH单独应用及与免疫检查点联合应用的疗效 抗体在转移性疾病中的作用评估我们的假设，即FLASH联合PD-1阻滞剂 将表现出协同抗肿瘤作用，由于增强系统范围的免疫反应，我们将研究 FLASH单独使用和与抗PD-1联合使用对辐射野外肿瘤的影响，并评估 如目标1中的免疫应答。目的3：明确FLASH的免疫细胞和分子基础 功效我们将测试的假设，即疗效是依赖于T细胞以及抗原呈递 树突状细胞（DCs）分别通过治疗Rag-2 KO和BATF 3 KO小鼠的肿瘤，并将阐明 通过将T细胞或DC从成功治疗的小鼠转移到用 肿瘤预期有效性所需的特定亚组是那些在多种组织中扩增的亚组 目标1。最后，我们将探讨I型干扰素及其受体在FLASH疗效中的作用。 预期结果和影响：预计这些实验将证明， 检查点疗法可促进原发性和转移性肿瘤的持久肿瘤消退， 损伤正常组织，从而为在临床试验中评估FLASH奠定基础。

Project Summary/Abstract Background: Radiation therapy (RT) is a core treatment modality that benefits patients with many types of cancer and can synergize with immune checkpoint blockade therapy. However, delivery of maximally effective doses of radiation to tumors is limited by collateral damage to normal tissues. We are developing a next- generation clinical RT platform called PHASER that will deliver ultra-rapid and precise radiation (FLASH) to decrease damage to normal tissues dramatically. Using a unique preclinical FLASH irradiator we developed for mice, our preliminary data show enhanced tumor control with FLASH vs. conventional dose rate irradiation as well as increased infiltration of immune cells into the tumor, suggestive of an immune mediated mechanism. Hypothesis and objective: We hypothesize that FLASH will demonstrate a superior therapeutic index by comparison to conventional dose rate RT for multiple cancers, based not only on its precision but also on the induction of more potent anti-tumor immunity. We will test this hypothesis in experimental models of cancer. Specific Aims and Study Design: Aim 1: Compare the anti-tumor potency, safety and immunological effects of FLASH vs conventional dose rate RT in primary tumors: We will evaluate different doses of FLASH and compare its effects with maximally tolerated doses of conventional dose rate RT in both syngeneic and patient derived xenograft mouse models. In addition to assessing tumor growth, we will analyze the effects of FLASH on the immune response, both locally and systemically through the use CyTOF and our SCAFFOLDS algorithms. This approach will reveal where and which immune cell subsets become activated in successfully treated animals. We will also assess the immunologic correlates of reduced toxicity from FLASH. Aim 2: Analyze the therapeutic effects of FLASH alone and in combination with immune checkpoint antibodies in metastatic disease. To assess our hypothesis that FLASH in combination with PD-1 blockade will exhibit synergistic anti-tumor effects due to an enhanced system-wide immune response, we will study the effects of FLASH, alone and in combination with anti-PD-1, on tumors outside the radiation field, and assess the immune response as in Aim 1. Aim 3: Identify the immune cellular and molecular basis of FLASH efficacy. We will test the hypothesis that efficacy is dependent on T cells as well as antigen presenting dendritic cells (DCs) by treating tumors in Rag-2 KO and BATF3 KO mice, respectively, and will elucidate the role for these cells by transferring T cells or DCs from successfully treated mice to naive mice challenged with tumor. The specific subsets required for efficacy are expected to be those shown to expand in multiple tissues in Aim 1. Lastly, we will explore the role of Type I interferon and its receptor on DCs in the efficacy of FLASH. Expected Results and Impact: These experiments are expected to demonstrate that FLASH in combination with checkpoint therapy promotes durable tumor regression of primary and metastatic tumors with little damage to normal tissues, thus setting stage for evaluating FLASH in clinical trials.