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: 10599538
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 10.51万
• 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/10599538
• 关键词: Ablation; Address; Biomedical Research; Blocking Antibodies; Brain; C57BL/6 Mouse; Cell Death; Cells; Clinical; Cognition; DNA Repair; Development; Disease; Dose; Dose-Rate; Faculty; Formalin; Funding; Gastrointestinal tract structure; Growth; Harvest; Hour; Image; Image Analysis; Immune; Immune response; Immune system; Immunohistochemistry; Immunologics; Immunotherapy; Infiltration; Inflammatory; Injections; Lead; Lewis Lung Carcinoma; MC38; Malignant Neoplasms; Measurement; Measures; Methods; Microscopy; Modality; Modeling; Mus; Normal tissue morphology; Paraffin Embedding; Parents; Patients; Positioning Attribute; Postdoctoral Fellow; Process; Pulmonary Fibrosis; Radiation; Radiation Dose Unit; Radiation Tolerance; Radiation therapy; Research; Skin; Stains; Syndrome; System; Testing; Therapeutic Effect; Therapeutic Studies; Time; Tissues; Toxic effect; Treatment Efficacy; anti-tumor immune response; base; cancer radiation therapy; cancer type; colon cancer cell line; comparative efficacy; digital imaging; experimental study; immune checkpoint; immunogenic; improved; in situ vaccination; inhibitor; intestinal crypt; irradiation; millimeter; mouse model; neoplastic cell; neuroinflammation; next generation; organ injury; pre-clinical; radioresistant; response; subcutaneous; synergism; tumor; tumor growth; tumor microenvironment

PROJECT ABSTRACT Radiation therapy is a core treatment modality that benefits patients with many types of cancer, and recent studies show that RT can enhance the efficacy of immune checkpoint blocking antibodies by inducing immunogenic tumor cell death and “in situ vaccination”. We recently discovered that higher doses of RT given over a smaller number of fractions ("accelerated fractionated RT") can cure single tumors in mouse models and that such cures rely on enhanced anti-tumor immune responses. Although the dose of RT was limited by damage to surrounding tissues, these findings raised the prospect of more robust responses and even cures of metastatic disease provided that we can understand how to optimize RT for maximum synergy with immunotherapy and minimize collateral damage. Based on this premise, we began developing a next-generation clinical radiation therapy platform that can deliver ultra-rapid radiation (FLASH) and complete treatment in less than a second for extremely precise RT, addressing the challenge of hitting moving targets like tumors and enabling safe delivery of higher RT doses. We have already developed a unique preclinical FLASH irradiator for mice and demonstrated enhanced tumor control and increased immune cell infiltration with FLASH vs. conventional dose rate irradiation (i.e., sub-second vs. 5-minute delivery of the same radiation doses) in a syngeneic subcutaneous tumor model. Prior studies in our lab and others also demonstrated dramatically decreased normal organ injury with FLASH in multiple systems, all of which have an inflammatory basis, including lung (fibrosis), brain (cognition and neuroinflammation) and GI tract (intestinal crypt ablation and GI syndrome). This R01 diversity supplement will support a new project, to be conducted by Dr. Soto, that is related to Aims 1 and 3 of the parent R01. One aim will examine the curative potential of FLASH radiation by identifying a radiation dose at which local tumor cure is achieved in subcutaneous tumor mouse models. This will build on Aim 1 of the parent R01 by further studying the therapeutic effect of FLASH radiation, not in the context of tumor growth delay, but rather in the context of tumor cure. The second aim will investigate the levels of activated TGF after FLASH radiation and compare them to levels of activated TGF following CONV radiation. Activated TGF has been shown to support tumor survival by enhancing DNA repair, suppressing the immune response, and promoting a growth-favorable tumor microenvironment (6). This will build on Aim 3 of the parent R01 by helping to understand a potential cellular mechanism for the efficacy of FLASH radiation.

项目摘要 放射治疗是一种核心治疗方式，使许多类型的癌症患者受益于 最近的研究表明，RT可以增强免疫检查点阻塞的功效 通过诱导免疫原性细胞死亡和“原位疫苗接种”抗体 发现较高剂量的RT给出了较少数量的分数 分离的RT”）在小鼠模型中固化单肿瘤，并且这种治疗方法依赖于 增强的抗肿瘤免疫反应。 周围的组织，这些发现弥漫了更多的呼吸反应的前景，甚至 如果我们可以理解如何优化RT以最大程度地优化转移性疾病 通过免疫疗法的协同作用，根据前提来最大程度地减少抵押品的损害。 开发下一代临床放射治疗平台，该平台可以提供超高 辐射（闪光灯）和在不到一秒钟的时间内完成治疗，对于极其精确的RT， 应对达到肿瘤等移动目标的挑战并实现安全交付 较高的RT剂量。 并显示出增强的肿瘤控制和通过闪光的免疫细胞浸润增加 vs.常规剂量率辐射（即，次秒与5分钟的递送相同 辐射剂量）在同步皮下肿瘤模型中。 在多个系统中，由于闪光的闪光造成的正常器官损伤也大大减少了 所有的HICH都有炎症基础，倾斜的肺（纤维化），大脑（认知和） 神经炎症）和胃肠道（肠道隐形和GI综合征） 补充剂将支持由Soto博士进行的一个新项目，该项目与目标1有关 和3个母体R01。 确定在皮下肿瘤小鼠中实现局部肿瘤治愈的辐射剂量 模型。 闪光辐射，不是在肿瘤生长延迟的背景下，而是在肿瘤的背景下 治愈。 将它们与激活辐射后的活化助剂TGF相比。 通过增强DNA修复，抑制免疫反应，证明可以支持肿瘤存活。 并促进有利于生长的肿瘤微环境（6）。 母体R01通过帮助了解闪光功效的潜在细胞机制 辐射。