Effects of FLASH Radiation on Cancer and the Immune Response

项目摘要/摘要 背景：放射治疗(RT)是一种核心治疗方式，可使多种类型的癌症患者受益。 并可与免疫检查点阻断治疗协同作用。然而，交付最有效的 对肿瘤的辐射剂量受到对正常组织的附带损害的限制。我们正在开发下一款- 名为PHASER的新一代临床RT平台将向 显著减少对正常组织的损害。使用我们为其开发的独特的临床前闪光辐射器 我们的初步数据显示，闪光照射与传统剂量率照射相比，肿瘤控制得到了增强 以及免疫细胞对肿瘤的渗透增加，提示存在免疫调节机制。 假设和目的：我们假设闪光通过以下方式显示出更好的治疗指标 与传统剂量率RT用于多种癌症的比较，不仅基于其精确度，还基于 诱导更强的抗肿瘤免疫。我们将在癌症的实验模型中检验这一假设。 具体目标和研究设计：目标1：比较两种药物的抗肿瘤效力、安全性和免疫学 闪光照射与常规剂量率放射治疗对原发肿瘤的影响：我们将评估不同剂量的 并将其效果与两种同基因小鼠常规剂量率RT的最大耐受剂量进行比较 和患者来源的异种移植小鼠模型。除了评估肿瘤生长外，我们还将分析 局部和全身免疫反应的闪光，通过使用细胞和我们的 脚手架算法。这种方法将揭示在哪里以及哪些免疫细胞亚群被激活 成功地治疗了动物。我们还将评估闪光毒性降低的免疫学相关性。 目的2：分析闪光照射与免疫检查点联合应用的疗效 转移疾病中的抗体。来评估闪光结合PD-1阻滞剂的假说 由于增强了全系统的免疫反应，将显示出协同的抗肿瘤作用，我们将研究 闪光单独和联合抗PD-1对照射野外肿瘤的影响，并评估 目标1.目标3：确定闪光的免疫细胞和分子基础 功效。我们将检验这一假设，即疗效取决于T细胞和抗原提呈 树突状细胞(DC)分别治疗RAG-2KO和BATF3KO小鼠的肿瘤，并将阐明 通过将成功治疗的小鼠的T细胞或DC转移到未成熟的小鼠身上而发挥作用 肿瘤。功效所需的特定亚群预计是那些在多个组织中扩张的亚群 目的1。最后，我们将探讨I型干扰素及其受体在闪光治疗中的作用。 预期结果和影响：这些实验有望证明闪存组合 使用检查点治疗促进原发和转移性肿瘤的持久肿瘤消退 对正常组织的损害，从而为在临床试验中评估闪光奠定了基础。

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.