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，可以使多种类型的患者受益。 癌症，可以与免疫检查点阻断疗法产生协同作用。然而，提供最大有效 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 - 称为 PHASER 的新一代临床 RT 平台，将提供超快速和精确的辐射 (FLASH) 显着减少对正常组织的损害。使用我们开发的独特的临床前 FLASH 照射器 小鼠，我们的初步数据显示，与传统剂量率照射相比，FLASH 增强了肿瘤控制 以及免疫细胞向肿瘤的浸润增加，表明存在免疫介导机制。 假设和目标：我们假设 FLASH 将通过以下方式表现出优越的治疗指数： 与多种癌症的常规剂量率 RT 进行比较，不仅基于其精度，还基于 诱导更有效的抗肿瘤免疫。我们将在癌症实验模型中检验这一假设。 具体目标和研究设计： 目标 1：比较抗肿瘤效力、安全性和免疫学 FLASH 与传统剂量率 RT 对原发性肿瘤的影响：我们将评估不同剂量的 FLASH 并比较其与两种同系药物中常规剂量率 RT 的最大耐受剂量的效果 和患者衍生的异种移植小鼠模型。除了评估肿瘤生长之外，我们还将分析效果 通过使用 CyTOF 和我们的技术，FLASH 对局部和全身免疫反应的影响 脚手架算法。这种方法将揭示免疫细胞亚群在何处以及哪些免疫细胞亚群在 成功治疗动物。我们还将评估 FLASH 毒性降低的免疫相关性。 目标2：分析FLASH单独使用以及联合免疫检查点的治疗效果 转移性疾病中的抗体。评估我们的假设，即 FLASH 与 PD-1 阻断相结合 由于增强的全系统免疫反应，将表现出协同抗肿瘤作用，我们将研究 单独使用 FLASH 以及与抗 PD-1 联合使用对放射野外肿瘤的影响，并评估 目标 1 中的免疫反应。目标 3：确定 FLASH 的免疫细胞和分子基础 功效。我们将检验功效取决于 T 细胞以及抗原呈递的假设 树突状细胞（DC）分别治疗 Rag-2 KO 和 BATF3 KO 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 转移到接受 肿瘤。功效所需的特定子集预计将是那些显示出在多个组织中扩展的子集 目标1。最后，我们将探讨I型干扰素及其在DC上的受体在FLASH疗效中的作用。 预期结果和影响：这些实验预计将证明 FLASH 与 检查点疗法可促进原发性和转移性肿瘤的持久消退，几乎不需要 正常组织损伤，从而为临床试验中评估 FLASH 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.