Effects of FLASH Radiation on Cancer and the Immune Response

项目摘要 放射治疗是一种核心治疗方式，使多种癌症患者受益， 最近的研究表明，RT可以增强免疫检查点阻断的效果 抗体通过诱导免疫原性肿瘤细胞死亡和“原位接种”。我们最近 研究发现，较高剂量的RT在较小数量的部分中给予(加速 分割RT“)可以治愈小鼠模型中的单个肿瘤，这种治疗依赖于 增强抗肿瘤免疫反应。尽管RT的剂量受到以下损害的限制 在周围组织中，这些发现可能会引起更强烈的反应，甚至 如果我们能理解如何最大限度地优化RT，就可以治愈转移性疾病 与免疫疗法协同作用，将附带损害降至最低。基于这个前提，我们开始 开发新一代临床放射治疗平台，提供超快速 放射(闪光)和在不到一秒的时间内完成治疗，实现极其精确的RT， 应对打击肿瘤等移动目标的挑战，并实现安全交付 更高的RT剂量。我们已经为小鼠开发了一种独特的临床前闪光照射器 并用闪光灯显示了增强的肿瘤控制和增加的免疫细胞渗透 与传统剂量率照射相比(即，亚秒级与5分钟级的辐射 辐射剂量)在同种皮下肿瘤模型中。我们实验室和其他实验室的先前研究 也显示了在多个系统中使用闪光显著减少了正常器官损伤， 所有这些都有炎症基础，包括肺(纤维化)、脑(认知和 神经炎)和胃肠道(肠隐窝消融术和胃肠道综合征)。此R01多样性 增刊将支持索托博士将开展的一个新项目，该项目与AIMS 1有关 亲本R01的3个。其中一个目标将通过以下方式检查闪光辐射的治疗潜力 确定皮下肿瘤小鼠局部治愈肿瘤的辐射剂量 模特们。这将建立在亲本R01的目标1的基础上，通过进一步研究 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 解药。第二个目的是研究闪光照射后活化的转化生长因子水平和 将它们与照射后激活的转化生长因子水平进行比较。激活的转化生长因子已被 显示通过增强DNA修复，抑制免疫反应来支持肿瘤存活， 促进有利于肿瘤生长的微环境(6)。这将建立在 亲本R01通过帮助理解闪光疗效的潜在细胞机制 辐射。

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.