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

第一个NHS高能质子治疗中心将于2018年在克里斯蒂开放。与传统的基于X射线的放射治疗相比，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几乎世纪使用X射线治疗癌症患者的经验。然而，人们普遍认为，由于对患者的剂量输送机制根本不同，对质子照射的生物反应与对X射线（光子）照射的生物反应不同。利用这种差异来提高质子治疗能力的潜力目前尚未开发。人们普遍认为，放射治疗的成功也涉及免疫系统。DNA损伤诱导的免疫激活有助于遗传毒性癌症治疗的功效，但其诱导的事件仍然知之甚少。当与免疫治疗联合使用时，存在将放射治疗转化为高效全身治疗的潜力，以改善大多数接受免疫治疗的癌症患者的结局，但需要进一步研究放射治疗和免疫治疗的最佳放射剂量和时间表[4]。肿瘤免疫原性反应的机制是复杂的，涉及许多重叠的机制和混杂因素。该项目的目的是在开发数学模型方面迈出第一步，该模型研究辐射的质量如何影响DNA损伤介导的反应的幅度，这是免疫原性反应的前兆。了解这第一步所涉及的机制是必不可少的，使一个更大的身体的工作要在曼彻斯特进行调查的免疫原性后果的质子therapeutic.Some authors报告说，免疫原性反应质子治疗上级X射线治疗，虽然缺乏系统的，定量的数据。该项目旨在解决的关键问题是：1。质子和X射线照射后不同的初始免疫应答的原因和机制是什么？2.我们能否利用质子免疫应答，在质子治疗计划、每次剂量和分次时间表方面优化质子治疗作为全身治疗的递送？

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?