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， 最近的研究表明，RT可以增强免疫检查点阻断的功效， 通过诱导免疫原性肿瘤细胞死亡和“原位疫苗接种”产生抗体。我们最近 发现在较少的分数中给予较高剂量的RT（“加速”）， 分级RT”）可以治愈小鼠模型中的单个肿瘤，并且这种治愈依赖于 增强抗肿瘤免疫应答。虽然RT的剂量受到损伤的限制， 这些发现提出了更有力的反应的前景， 转移性疾病的治愈，前提是我们能够了解如何优化RT， 与免疫疗法协同作用并使附带损害最小化。基于这个前提，我们开始 开发下一代临床放射治疗平台， 在不到一秒的时间内完成治疗，实现极其精确的RT， 解决击中肿瘤等移动目标的挑战，并实现安全递送 更高的RT剂量。我们已经为小鼠开发了一种独特的临床前FLASH辐照器 并显示出增强的肿瘤控制和增加的免疫细胞浸润与FLASH vs.常规剂量率辐射（即，亚秒与5分钟的交付 辐射剂量）。我们实验室和其他实验室的先前研究 也证明了FLASH在多个系统中显著降低了正常器官损伤， 所有这些疾病都有炎症基础，包括肺（纤维化）、脑（认知和 神经炎症）和胃肠道（肠隐窝消融和GI综合征）。R01多样性 补充资金将用于支持一个新项目，该项目将由Soto博士主持，与目标1有关 和亲本R01的3个。一个目标是通过以下方式来检查闪光辐射的治疗潜力： 确定在皮下肿瘤小鼠中实现局部肿瘤治愈的辐射剂量 模型这将建立在母体R01的目标1的基础上，通过进一步研究 FLASH辐射，不是在肿瘤生长延迟的背景下，而是在肿瘤生长延迟的背景下， 疗方第二个目标是研究FLASH辐射后活化的TGF β 1的水平， 将它们与CONV辐射后活化的TGF β 1水平进行比较。活化的TGF β 1已被 通过增强DNA修复，抑制免疫反应， 和促进生长有利的肿瘤微环境（6）。这将建立在目标3的基础上 通过帮助理解FLASH疗效的潜在细胞机制， 辐射