Effects of FLASH Radiation on Cancer and the Immune Response

闪光辐射对癌症和免疫反应的影响

• 批准号: 10429937
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 48.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429937
• 关键词: Ablation; Abscopal effect; Address; Algorithms; Animals; Antibodies; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Background Radiation; Blocking Antibodies; Brain; Cancer Model; Cell Death; Cells; Clinical; Clinical Trials; Cognition; Data; Dendritic Cells; Disease; Distant; Dose; Dose-Rate; Exhibits; Experimental Models; Gastrointestinal tract structure; Human; Immune; Immune response; Immune system; Immunologics; Immunotherapy; Infiltration; Inflammatory; Interferon Type I; Knockout Mice; Linear Accelerator Radiotherapy Systems; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Medical; Modality; Modeling; Molecular; Mus; Neoplasm Metastasis; Normal tissue morphology; PD-1 blockade; Patients; Pharmacology; Primary Neoplasm; Pulmonary Fibrosis; Radiation; Radiation Dose Unit; Radiation therapy; Research Design; Role; Safety; Suggestion; Syndrome; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic Index; Tissues; Toxic effect; Tumor Immunity; Tumor-infiltrating immune cells; anti-PD-1; anti-PD1 antibodies; anti-tumor immune response; antitumor effect; base; cancer radiation therapy; cancer type; checkpoint therapy; expectation; experimental study; fractionated radiation; immune checkpoint; immune checkpoint blockade; immunogenic; in situ vaccination; intestinal crypt; irradiation; lymphocyte trafficking; mouse model; neoplastic cell; neuroinflammation; next generation; organ injury; patient derived xenograft model; pre-clinical; receptor; response; subcutaneous; synergism; tumor; tumor eradication; tumor growth

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.

项目摘要/摘要 背景：放射疗法（RT）是一种核心治疗方式，使许多类型的患者受益 癌症，可以与免疫检查点阻滞疗法协同作用。但是，交付最大有效 对肿瘤的辐射剂量受到正常组织的附带损害的限制。我们正在开发下一个 称为Phaser的生成临床RT平台，它将将超优化和精确的辐射（闪光灯）传递到 大大减少对正常组织的损害。使用我们为 小鼠，我们的初步数据显示，通过闪光与常规剂量率照射增强了肿瘤控制 以及增加免疫细胞进入肿瘤的浸润，提示免疫介导的机制。 假设和客观：我们假设闪光灯将通过 与多种癌症的常规剂量率RT进行比较，不仅是基于其精度，而且还基于 诱导更有效的抗肿瘤免疫力。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：目标1：比较抗肿瘤效力，安全性和免疫学 闪光与常规剂量率RT在原发性肿瘤中的影响：我们将评估不同剂量的 闪光并将其效果与两种同步性的最大耐受剂量的常规剂量率RT进行比较 和患者衍生的异种移植小鼠模型。除了评估肿瘤生长外，我们还将分析这些影响 通过使用Cytof和我们 脚手架算法。这种方法将揭示在何处和哪些免疫细胞子集被激活 成功治疗的动物。我们还将评估闪光毒性降低的免疫学相关性。 目标2：单独分析闪光的治疗作用，并与免疫检查点结合 转移性疾病中的抗体。评估我们的假设，即闪光与PD-1封锁结合 由于系统范围的免疫反应增强，将表现出协同的抗肿瘤作用，我们将研究 闪光灯，单独并与抗PD-1结合的影响，对辐射场外的肿瘤进行评估 AIM 1中的免疫反应。目标3：识别闪光的免疫细胞和分子基础 功效。我们将检验以下假设，即功效取决于T细胞以及抗原呈现 树突状细胞（DC）分别通过治疗RAG-2 KO和BATF3 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受到挑战的天真小鼠，使这些细胞的作用 瘤。预计有疗效所需的特定子集将是显示在多个组织中扩展的那些子集 在AIM 1中。最后，我们将探讨I型干扰素及其受体在闪光灯功效中的作用。 预期结果和影响：这些实验有望证明该闪光合并 使用检查点疗法可促进原发性和转移性肿瘤的耐用肿瘤回归，很少 对正常组织的损害，因此在临床试验中设定了评估闪光的阶段。