High dose rate irradiator platform to investigate the mechanisms of FLASH radiotherapy

放射疗法是一种非常有效的抗癌治疗方法，但其使用与对正常组织的显著损伤的风险相关，这可能导致长期的副作用。近年来，人们对整合激活免疫系统的新癌症治疗（所谓的免疫疗法）以及放射疗法以“接种”患者对抗自身癌症的兴趣浓厚。到目前为止，这些组合的临床试验结果相当矛盾，有些显示出益处，而另一些则没有。事实上，有人担心，对肿瘤和附近淋巴结的辐射实际上可能损害人们试图引发的免疫反应，新技术提供了一个前景，即保持辐射的有利的直接抗肿瘤效果，同时减少对正常组织的损害，包括免疫细胞和支持肿瘤的细胞（所谓的基质）。我们建议使用一个技术平台，小动物辐射研究平台或SARRP，来测试两种特定的方法来保护免疫系统免受辐射引起的损伤。这些技术被称为闪烁剂量率（或FLASH）和空间剂量调制（或SDM）。使用FLASH，剂量在几分之一秒（毫秒或更短）内给出，而不是像传统剂量率那样在几分钟内给出。在SDM放射治疗中，与既定实践相反，我们避免试图均匀地照射肿瘤的每个部分。相反，我们故意在肿瘤的波峰和波谷中不均匀地给予放射治疗，依赖于照射部分引起的损伤足以触发清除未照射部分的过程。这两种方法都可以减少正常组织的损伤，但它们在保持肿瘤控制的同时实现这种效果的机制在很大程度上是未知的。这项申请资助的新技术将使我们能够首次评估以FLASH剂量率（影响时间因素）进行辐射的差异效应，SDM放射治疗（影响空间因素）或以FLASH剂量率（影响时空因素）进行部分肿瘤照射的双模式（SDM模式）。为了使用能够在动物模型中提供空间调制放射治疗的新SARP-FLASH，我们需要解决许多物理/工程相关的问题，包括能够在时间和空间上准确测量我们提供的剂量，以及能够在照射期间同时整合FLASH和SDM效应。在此之后，我们将分析每个组件，FLASH和SDM，作为单一的方式或作为一个新的FLASH-SDM技术相结合的效果。在所有情况下，我们比较结果的金标准将是常规剂量率下的全肿瘤（所谓的宽束）放射治疗。我们将使用成熟的实验室技术来测量不同辐射技术对肿瘤成分的影响，分别分析肿瘤，免疫和基质（成纤维细胞）细胞。新的SARRP-FLASH平台将使我们能够观察单独辐射和辐射与药物治疗（包括免疫治疗）联合使用的效果。我们有机会获得动物模型，这将使我们能够了解FLASH和SDM对免疫细胞进出肿瘤的迁移的影响，包括附近的淋巴结（免疫反应的编组场），以及对肿瘤内外免疫细胞的激活状态的影响。最后，在准备翻译给患者时，我们将评估如何使用磁共振成像和超声扫描来测量FLASH、SDM和FLASH-SDM的效果。这些研究将使我们能够提出所谓的生物标志物，这些生物标志物将预测谁将从这些新的治疗方法中受益，以及如何优化其效果，以增强对癌细胞的直接和免疫相关的杀伤。

Radiation therapy is a highly effective anti-cancer treatment, but its use is associated with risks of significant damage to normal tissues which can lead to long-term side effects. In recent years, there has been great interest in integrating new cancer treatments that activate the immune system, so-called immunotherapy, alongside radiation therapy to "vaccinate" patients against their own cancers. Thus far, results from clinical trials of such combinations have been rather contradictory, with some showing benefit and others failing to do so. Indeed, there are concerns that the radiation delivered to the tumour and nearby lymph nodes may, in fact, damage the very immune response one is trying to trigger.New technologies offer the prospect of maintaining the favourable direct anti-tumour effects of radiation and, simultaneously, reducing damage to normal tissues, including immune cells and those that support the tumour (the so-called stroma). We propose to use a technology platform, the small animal radiation research platform or SARRP, to test two specific approaches to sparing the immune system from radiation-induced damage. The techniques are called ultrahigh dose-rate (or FLASH) and spatial dose modulation (or SDM). With FLASH, the dose is given in tiny fractions of a second (milliseconds or less) rather than over minutes, as with conventional dose-rates. In SDM radiotherapy, in contrast to established practice, we avoid trying to irradiate every part of the tumour evenly. Instead, we deliberately give the radiotherapy unevenly in peaks and troughs across the tumour, relying on the damage caused in the irradiated part to be sufficient to trigger processes that clear the unirradiated portion. Both approaches can reduce normal tissue damage, but the mechanisms by which they achieve such effects, while maintaining tumour control, are largely unknown. The new technology funded by this application will allow us, for the first time, to evaluate differential effects of giving radiation at FLASH dose-rates (affecting temporal factors), by SDM radiotherapy (affecting spatial factors) or as dual-modality of partial tumour irradiation (SDM mode) at FLASH dose-rates (affecting spatio-temporal factors). In order to use the new SARRP-FLASH that is capable of delivering spatially modulated radiotherapy in animal models, we will need to solve a number of physics/engineering-related problems, including being able to measure the doses we deliver accurately in time and space and being able to integrate both the FLASH and SDM effects at the same time during an episode of irradiation. After that, we will analyse the effects of each of the components, FLASH and SDM, as single modalities or combined as a novel FLASH-SDM technique. In all cases, the gold-standard against which we compare our results will be whole tumour (so-called broad-beam) radiotherapy at conventional dose-rates. We will use well-established lab techniques to measure the effects of the different radiation techniques on components of the tumour, separately analysing tumour, immune and stromal (fibroblast) cells. The new SARRP-FLASH platform will allow us to look at effects of radiation alone and radiation combined with drug therapies (including immunotherapies). We have access to animal models that will allow us to understand the effects of FLASH and SDM on the migration of immune cells in and out of the tumour, including to nearby lymph nodes (the marshalling yards of immune responses), and on the activation status of immune cells inside and outside the tumour. Finally, in preparation for translation to patients, we will evaluate how to use magnetic resonance imaging and ultrasound scans to measure the effects of FLASH, SDM and FLASH-SDM. These studies will allow us to propose so-called biomarkers that will predict who will benefit from these new treatment approaches and how to optimise their effects to enhance direct and immune-related killing of cancer cells.