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

高剂量率辐照平台研究FLASH放疗机制

• 批准号: MR/X013006/1
• 负责人: Uwe Oeflke
• 金额: $ 101.94万
• 依托单位: Institute of Cancer Research
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX013006%2F1
• 关键词: dose; rate; irradiator; platform; investigate

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.

放射治疗是一种高效的抗癌疗法，但它的使用与对正常组织造成重大损害的风险有关，这可能会导致长期的副作用。近年来，人们对将激活免疫系统的新癌症治疗方法--即所谓的免疫疗法--与放射疗法相结合，为患者接种针对自己癌症的疫苗一直很感兴趣。到目前为止，这些组合的临床试验结果相当矛盾，一些显示出好处，另一些则没有做到这一点。事实上，人们担心，辐射到肿瘤和附近淋巴结的辐射实际上可能会损害人们试图触发的免疫反应。新技术提供了一种前景，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组织(所谓的间质)。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，以防止免疫系统受到辐射诱导的损害。这些技术被称为超高剂量率(或闪光)和空间剂量调制(或SDM)。对于闪光灯，剂量是以极小的零点几秒(毫秒或更短)给出的，而不是像传统的剂量率那样以分钟为单位。在SDM放射治疗中，与既定的做法不同，我们避免试图均匀地照射肿瘤的每一个部分。相反，我们故意在整个肿瘤的波峰和波谷中进行不均匀的放射治疗，依赖于在照射部分造成的损害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的组织损伤，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尚不清楚。这项由该应用程序资助的新技术将使我们第一次能够评估以闪光剂量率(影响时间因素)、SDM放射治疗(影响空间因素)或以闪光剂量率给予局部肿瘤照射(SDM模式)(影响时空因素)的不同效果。为了在动物模型中使用能够提供空间调制放射治疗的新型SARRP-FLASH，我们将需要解决许多与物理/工程相关的问题，包括能够在时间和空间上准确地测量我们提供的剂量，以及能够在一次照射期间同时整合闪光和SDM效应。之后，我们将分析每个组件(闪存和SDM)作为单一模式或组合作为新的闪存-SDM技术的效果。在所有情况下，我们比较结果的金标准将是传统剂量率下的整个肿瘤(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放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平台将允许我们单独观察辐射的影响，以及辐射与药物疗法(包括免疫疗法)的结合。我们可以使用动物模型来了解闪光和SDM对免疫细胞在肿瘤内外迁移的影响，包括迁移到附近的淋巴结(免疫反应的编组码)，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闪光、SDM和闪光-SDM的效果。这些研究将使我们能够提出所谓的生物标记物，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，以加强对癌细胞的直接和免疫相关的杀伤。