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This invited review examines in silico models describing radiotherapy, immunotherapy, and patient immune interactions, focusing on mathematical models published in English. Results suggest improved predicted efficacy for combined treatment versus either modality alone, yet model disagreement persists regarding optimal scheduling and fractionation. The review links this discrepancy to differences in model approaches and cancer types, highlighting the need for further comparisons using similar datasets to identify the best model and regimen for specific cancers and stages.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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\n[https://doi.org/10.1007/s13246-024-01458-1](https://doi.org/10.1007/s13246-024-01458-1)  \nINVITED REVIEW  \nMechanistic in silico explorations ofthe immunogenic and synergistic effects of radiotherapy and immunotherapy: a critical review  \nAllison M. Ng1 · Kelly M. MacKinnon1,2 · Alistair A. Cook2,3,4 · Rebecca A. D’Alonzo1,2,3 · Pejman Rowshanfarzad1,5 · Anna K. Nowak2,3,6 · Suki Gill1,7 · Martin A. Ebert1,5,7  \nReceived: 12 February 2024 / Accepted: 17 June 2024 / Published online: 17 July 2024 © Crown 2024  \nAbstract  \nImmunotherapy is a rapidly evolving field, with many models attempting to describe its impact on the immune system, especially when paired with radiotherapy. Tumor response to this combination involves a complex spatiotemporal dynamic which makes either clinical or pre-clinical in vivo investigation across the resulting extensive solution space extremely difficult. In this review, several in silico models of the interaction between radiotherapy, immunotherapy, and the patient’s immune system are examined. The study included only mathematical models published in English that investigated the effects of radiotherapy on the immune system, or the effect of immuno-radiotherapy with immune checkpoint inhibitors. The findings indicate that treatment efficacy was predicted to improve when both radiotherapy and immunotherapy were administered, compared to radiotherapy or immunotherapy alone. However, the models do not agree on the optimal schedule and fractionation of radiotherapy and immunotherapy. This corresponds to relevant clinical trials, which report an improved treatment efficacy with combination therapy, however, the optimal scheduling varies between clinical trials. This discrepancy between the models can be attributed to the variation in model approach and the specific cancer types modeled, making the determination of the optimum general treatment schedule and model challenging. Further research needs to be conducted with similar data sets to evaluate the best model and treatment schedule for a specific cancer type and stage.  \nKeywords Cancer immunotherapy · Radiotherapy · Mathematical modelling · Treatment response  \n􀀍 Martin A. Ebert [Martin.Ebert@health.wa.gov.au](Martin.Ebert@health.wa.gov.au)  \n1 School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, WA, Australia  \n2 National Centre for Asbestos Related Diseases, The University of Western Australia, Crawley, WA, Australia  \n3 Institute for Respiratory Health, Institute for Respiratory Health, Perth, WA, Australia  \n4 School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia  \n5 Centre for Advanced Technologies in Cancer Research (CATCR), Perth, WA, Australia  \n6 Medical School, The University of Western Australia, Crawley, WA, Australia  \n7 Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia  \nIntroduction  \nThe benefits of radiation therapy (RT) for the treatment of localized cancer include its spatially-localized ablative properties; the induction of localized, catastrophic damage to the tumoral DNA and subsequent cell death. A component of this cell killing is now understood to be a result of the immunogenic nature of radiation-induced cell death [7] . This can induce local bystander and, rarely, remote abscopal effects, where a tumor outside the irradiated region regresses [18] . However, there is a lack of an enduring response in a clinical setting [62] .  \nThe addition of immune checkpoint inhibitors (ICIs) capitalizes upon the inflammatory environment induced post-RT. Clinical trials in multiple cancer types have shown improvement in patient outcomes when both immunotherapy (IO) and RT are administered [30, 35, 51, 56] . The mechanisms underlying RT/ICI synergy are poorly understood, and the factors necessary to optimize the treatment  \neven less so. ICI monotherapy itsel","cbCaihEHMa0mROs7","https://ap.wps.com/l/cbCaihEHMa0mROs7","pdf",1627915,16,"English","# Abstract\n# Introduction\n## Radiation therapy benefits and immunogenic cell death\n## Immune checkpoint inhibitors and synergy rationale\n## Challenges in biomarkers and predicting side effects\n## Need to determine schedules and tumor microenvironment\n## Role of in silico modeling and standardization","[{\"question\":\"What is the main aim of this review?\",\"answer\":\"To summarize in silico radiotherapy (RT) and immuno-radiotherapy (IO-RT) treatment models and consolidate current approaches, while encouraging standardization of reporting for non-diagnostic computational models.\"},{\"question\":\"What do the reviewed in silico models generally predict about combination therapy?\",\"answer\":\"Treatment efficacy is predicted to improve when radiotherapy and immunotherapy are administered together compared with radiotherapy or immunotherapy alone.\"},{\"question\":\"Why do the models disagree on the optimal RT/IO schedule?\",\"answer\":\"The review attributes the mismatch to variations in model approach and the specific cancer types modeled, making it challenging to determine a single optimum general treatment schedule.\"}]","Mechanistic in silico explorations of the immunogenic and synergistic effects of radiotherapy and immunotherapy: a critical review | PDF",1789999841]