ESTRO 38 Abstract book

S232 ESTRO 38

hypo-fractionated regimen, ideally with 3-5 doses of less than 10-12 Gy each, should be used when radiotherapy is combined with immunotherapy. Recent clinical data confirms the use of this dose and fractionation regimens, demonstrating efficacy in human cancers (Nature Medicine 2018:24, 1845-51).

lack of published randomized trials comparing E-HF with C-F and/or M-HF, suggest that E-HF should remain an area of investigation. The aim of this teaching lecture is to review the present clinical experience of extreme hypofractionation in localized prostate cancer, discussing patient and disease selection, different fractionation schemes, major technical features of available treatments, the present evidence re toxicities and oncologic outcomes , and future developments in the use of E-HF.

Teaching Lecture: Tumor metabolism and radiation response

SP-0441 Inhibiting mitochondrial TCA cycle unravels tumor growth inhibitory and radiosensitizing effects O. Feron 1 1 UCLouvain, Institut De Recherche Expérimentale Et Clinique Irec, Brussels, Belgium Abstract text Lactate exchange between glycolytic and oxidative cancer cells optimizes tumor growth. Blocking lactate uptake through monocarboxylate transporter 1 (MCT1) thus represents an attractive therapeutic strategy but may in turn stimulate glucose consumption by oxidative cancer cells. Here, we found that inhibition of mitochondrial pyruvate carrier (MPC) activity could fulfill the tasks of blocking lactate use while preventing glucose oxidative metabolism. Using in vitro 13 C-glucose and in vivo hyperpolarized 13 C-pyruvate, we identified 7ACC2 as a potent inhibitor of mitochondrial pyruvate transport which consecutively blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation. Also while in spheroids MCT1 inhibition leads to cytostatic effects, pharmacological inhibition of MPC activity induces profound cytotoxic effects together with glycolysis stimulation and uncompensated inhibition of mitochondrial respiration. Hypoxia reduction obtained with 7ACC2 was further shown to sensitize tumor xenografts to radiotherapy. Hence, this study positions MPC as a control point not only for pyruvate but also lactate metabolism and expands on the radiosensitizing potential of MPC inhibition. SP-0442 Machine learning in radiomic analyses to predict radiotherapy outcome S. Löck 1 1 OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus- Technische Universität Dresden- Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany Abstract text This lecture will focus on specific methods for the development and validation of prognostic or predictive models based on features extracted from medical imaging. The radiomic workflow, starting from available medical images to finally validated models, will be presented. Different machine-learning algorithms for the tasks of feature selection and model development will be explained in detail. Furthermore, the steps of hyper- parameter tuning and model validation will be discussed. The results of systematic comparisons between machine- learning algorithms for the tasks of feature selection, patient classification or survival analysis allow for selecting suitable methods, which is an important step to increase the robustness of radiomic studies. After this lecture the participants may have a general impression on the radiomic workflow and on specific machine-learning algorithms applied for radiomic analyses. Teaching Lecture: Radiomic machine-learning to predict radiotherapy outcome

Teaching Lecture: Radio-immunotherapy: challenges and opportunities

SP-0440 Immunotherapy and Radiotherapy: challenges and opportunities S. Formenti 1 1 Weill Cornell Medical Center of Cornell University, Radiation Oncology, New York- NY, USA Abstract text Radiotherapy has revealed an ideal adjuvant to cancer immunotherapy, because of it's ability to convert the irradiated tumor into an individualized, in situ vaccine. When successful at immunizing, radiotherapy evokes T cell memory, and induces effects outside the treated field, defined as abscopal effects (responses at a distant, synchronous, un-irradiated established tumor or metastasis). In the setting of clinical cancer, however, abscopal effects are extremely rare, because of immune- suppressive characteristic of established solid tumors (Curr Probl Cancer 40;25-37, 2016). Thus, strategies to exploit the pro-immunogenic effects of radiotherapy require combination with immunotherapy: experiments in several syngeneic mouse models that mimic the setting of advanced cancer have demonstrated promise of combining radiation with immune checkpoint blockade (Clin Cancer Res. 2005;11:728-734). Radiation can compensate tumors with a low mutational load, by inducing de novo T cell priming to multiple tumor antigens and therefore, achieve responses in the absence of pre-existing neoantigens with anedoctal clinical examples confirming the preclinical data (Trends Cancer 2016:2,6:286-294). Currently, multiple clinical trials are exploring optimal regimes of radiotherapy and immunotherapy, with some initial success. The issue of dose and fractionation seems to be particularly relevant to abscopal responses. A mechanism underlying the dose dependence of abscopal response was recently elucidated (Nature Communications 2017; Jun 9;8:15618 ). In mice bearing bilateral TSA murine breast carcinoma when combined with ICB a single dose of 20 or 30Gy achieved comparable in field control to that of a regimen of 8GyX3 fractions, but only the fractionated regimen induced abscopal responses. Radiation-generated double strands (ds) DNA fragments reach the cytoplasm of irradiated cells where they are “sensed” by the cGAS/STING pathway (cGAS=cyclic GMP-AMP synthase and its adaptor protein STING= stimulator of interferon genes, aka transmembrane protein 173 – TMEM173). cGAS binds cytosolic dsDNA to initiate interferon (IFN-I) responses upon STING stimulation, resulting in dendritic cell recruitment and cross-priming of effector T-cells, the key steps to convert the tumor into an in situ vaccine. When tested in multiple carcinoma murine and human carcinoma cells as the radiation dose per fraction increases, cytosolic dsDNA was found to accumulate to a threshold above which induction of three prime repair exonuclease 1 (Trex1) occurred, an enzyme that degrades cytoplasmic DNA. Single doses in excess of 10-12Gy induced Trex1 to rapidly degrade cytosolic dsDNA, the substrate for cGAS/STING. As a result, signaling to induce IFN was abrogated, impairing RT-induced abscopal effects. Consideration to these findings suggest that a