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

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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?