Experimental and computational analysis of the cellular responses to proton beam therapy

首个NHS高能质子治疗中心将于2018年在克里斯蒂开业。与传统的x射线放射治疗相比，质子治疗是一种年轻的放射治疗技术。质子治疗的治疗计划是基于近一个世纪以来使用x射线治疗癌症患者的经验。然而，人们普遍认为，质子照射的生物反应与x射线（光子）照射的生物反应是不同的，因为给病人的剂量传递机制根本不同。利用这种差异来增强质子治疗能力的潜力目前尚未开发。人们普遍认为放射治疗的成功也与免疫系统有关。DNA损伤诱导的免疫激活有助于基因毒性癌症治疗的疗效，但其诱导的潜在事件仍然知之甚少。对于大多数接受免疫治疗的癌症患者来说，当与免疫治疗联合使用时，有可能将放射治疗转化为一种高效的全身治疗，以改善其预后，然而，关于放射治疗和免疫治疗[4]的最佳放射剂量和时间表还需要进一步的研究。肿瘤免疫原性反应的机制是复杂的，涉及许多重叠机制和混杂因素。该项目旨在为数学模型的发展迈出第一步，该模型研究辐射质量如何影响DNA损伤介导反应的大小，这是免疫原性反应的前兆。了解这第一步中涉及的机制对于在曼彻斯特开展更大规模的工作来研究质子治疗的免疫原性后果至关重要。一些作者报道，质子治疗的免疫原性反应优于x线治疗，尽管缺乏系统的定量数据。本项目旨在解决的关键问题是：1。质子照射与x射线照射初始免疫反应不同的原因和机制是什么？我们能否利用质子免疫反应来优化质子治疗作为一种全身治疗的输送，在质子治疗计划、每组分剂量和分馏时间表方面？

The first NHS high energy proton therapy centre will open at the Christie in 2018. Proton therapy is a young technology for radiotherapy in comparison to traditional X-ray based radiotherapy. The treatment planning for proton therapy is based on almost a century of experience treating patients for cancer using X-rays. However, it is widely recognised that the biological response to proton irradiation is different to the biological response to X-ray (photon) irradiation, due to the fundamentally different mechanisms of dose delivery to the patient. The potential to exploit this difference to enhance the therapeutic capability of proton therapy is currently un-tapped.It is accepted that the success of radiotherapy also involves the immune system. DNA damage induced immune activation contributes to the efficacy of genotoxic cancer therapy, yet the events underlying it's induction remain poorly understood. The potential exists to convert radiotherapy into a highly effective systemic therapy when used in combination with immunotherapy to improve the outcome for most cancer patients who receive immunotherapy, however further research is required regarding the optimal radiation dose and scheduling of radiotherapy and immunotherapy[4]. The mechanisms of tumour immunogenic response are complex, involving many overlapping mechanisms and confounding factors. This project aims to make a first step in the development of a mathematical model, which investigates how the quality of radiation can affect the magnitude of DNA damage mediated responses, a precursor to immunogenic response. Understanding the mechanisms involved in this first step is essential to enable a larger body of work to be undertaken in Manchester to investigate the immunogenic consequences of proton therapy.Some authors report that the immunogenic response to proton therapy is superior to that of X-ray therapy, although there is a lack of systematic, quantitative data. The key questions that this project aims to address are:1. What is the cause and mechanism of different initial immune responses between proton and X-ray irradiation?2. Can we exploit the proton-immuno response to optimise the delivery of proton therapy as a systemic therapy in terms of the proton treatment plan, dose per fraction and fractionation schedule?