ESTRO 36 Abstract Book

S310 ESTRO 36 _______________________________________________________________________________________________

doses (90Gy) can be achieved in big tumours, and if it is not used local control can decrease as much as 20%. On the other hand, smaller volumes can be radiated in nasopharynx, early bronchial and oesophageal carcinomas increasing the dose in cases where the tumor control is dose-dependent. BT allows better function performing smaller glossectomies in tongue carcinomas and with less xerostomy than SBRT, and with preservation of sphincter in anal canal cancer. Organs at risk are clearly preserved in prostate carcinoma delivering lower doses to rectum and bladder, as well as allowing focal therapy. Last but not least, the biological effect of BT due to the high dose inside the treated volume, can have an influence in decreasing the risk of relapse in breast carcinoma at long- term FU. Therefore, non-invasive techniques can b e more comfortable and desirable, but the main goal in oncology is long-term tumor control with minimal late effects in organs at risk, and BT in selected situations is still the best option nowadays. SP-0589 Molecular mechanisms of radiation-induced in situ tumor vaccination S. Demaria 1 1 Weill Cornell Medical College, Radiation Oncology and Pathology, New York, USA Growing pre-clinical and clinical evidence supports the hypothesis that ionizing radiation applied locally to a tumor has the ability to induce the activation of tumor- specific T cells. This property of radiation, which is likely responsible for the occasional occurrence of abscopal effects (regression of tumors outside of the radiation field), has attained increasing importance in the new era of immuno-oncology with radiotherapy being tested in a large number of clinical studies as a treatment that can increase patients responses to immunotherapy (1). In fact, radiation-induced in situ vaccination could provide a relatively simple and widely available modality to achieve the personalized immunization of a patient towards mutated proteins expressed by his/her tumor (2). Proof- of-principle evidence that radiotherapy in combination with immune checkpoint inhibitors elicits powerful and durable anti-tumor responses has been obtained in several pre-clinical models (3). However, the mechanisms underlying radiation’s ability to induce effective anti- tumor immune responses remain incompletely understood (4). My lab studies the radiation-induced molecular pathways responsible for effective activation of robust anti-tumor T cells that medicate abscopal effects. Recruitment to the tumor of a Batf3-dependent subset of dendritic cells specialized in cross-presentation of tumor-derived antigens to CD8 + cytotoxic T cells (CTLs) is driven by type I interferon (IFN-I) and has been shown to be essential for activation of anti-tumor CD8 + T cells. We have recently found that in tumors refractory to treatment with immune checkpoint inhibitors radiotherapy induces cancer cell- intrinsic activation of IFN-I pathway and release of interferon-beta, mimicking a viral infection, and resulting in recruitment of Batf3-dependent DCs. Importantly, the dose and fractionation of radiation are critical for induction of IFN-I production by irradiated cancer cells, with a lower (doses >2-4 Gy) and an upper (doses>12 Gy) threshold for the induction of IFN-I, creating a therapeutic window that defines the immunogenicity of radiotherapy. The molecular mechanisms that regulate this therapeutic window will be presented. Fractionation, i.e., repeated (three times) daily delivery of radiation therapy at doses within this window, amplifies the IFN-I pathway activation in the carcinoma cells, an effect that requires Symposium with Proffered Papers: Novel approaches in tumour control

upregulation of IFNRA. Furthermore, the synergy of radiation with immune checkpoint inhibitors and the induction of abscopal effects are completely dependent on the ability of radiotherapy to induce cancer cell- intrinsic IFN-I. These findings have critical implications for the use of radiotherapy to increase responses to immunotherapy in the clinic. Supported by NIH 1R01CA201246 and 1R01CA198533, Breast Cancer Research Foundation, and The Chemotherapy Foundation. References 1. Kang J, Demaria S, Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer. 2016;4:51. 2. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69-74. 3. Pilones KA, Vanpouille-Box C, Demaria S. Combination of radiotherapy and immune checkpoint inhibitors. Semin Radiat Oncol. 2015;25:28-33. 4. Demaria S, Coleman CN, Formenti S. Radiotherapy: Changing the Game in Immunotherapy. Trends in Cancer. 2016;2:286-94. SP- 0590 Novel developments in paediatric cancer M.G. McCabe 1 1 University of Manchester, Division of Molecular and Clinical Cancer Sciences, Manchester, United Kingdom The last decade has seen only incremental improvements in survival when compared to the dramatic changes that followed the centralisation of specialist care and the introduction of multi-agent chemotherapy regimens and combination treatments during the last half century. Although in some cases subtle, those incremental changes have been apparent across almost all types of childhood cancer, even the most refractory to change. Five-year overall survival for childhood cancer in the last EUROCARE cohort was just under 80%, and in many European countries now exceeds 80%. The explosion in high throughput '-omics' technologies and expertise currently underway is rapidly expanding our knowledge of the mechanistic drivers of tumour growth and treatment resistance. Progress is not evenly distributed across childhood cancer; the brain tumour community has benefited particularly from molecular technologies, with the recognition of some novel tumour entities, subclassification of others and the de- classification of one major tumour group altogether. More accurate recapitulation of tumour biology by in vivo models is also contributing to understanding of tumorigenesis and treatment effects, and holds promise for individually tailored therapies. Whilst molecular profiling has undoubtedly increased our ability to accurately diagnose and risk stratify tumours, and in many cases identified the mutations responsible for tumorigenesis, that knowledge has yet to lead to a paradigm shift in treatment for most paediatric cancers. Childhood cancers in general have fewer mutations than their adult counterparts and could be expected to have more sensitivity to appropriately targeted therapies. The challenges, however, are multifactorial: redundancy in signal transduction pathways, a predominance of driver mutations in genes encoding proteins that are difficult to target, tumorigenesis driven by missing tumour suppressor genes rather than over-expressed oncogenes, and a commercial and legislative environment that does not foster the development of novel therapies for rare cancers. Notwithstanding the challenges, progress is being on multiple fronts. There are examples of successful incorporation of molecular therapies into standard treatment in haematological and solid malignancies. Individual tumour profiling is becoming increasingly routine in clinical practice. Several European

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