ESTRO 37 Abstract book

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ESTRO 37

biology which sculpts the immune response against a tumour during therapy, an essential requirement if we are to fully exploit the potential of immunoradiotherapy. SP-0334 From local to abscopal: preclinical evidence that radiation dose and fractionation determine its synergy with immunotherapy S. Demaria 1 1 Weill Cornell Medical College, Department of Pathology, New York, USA Abstract text Most cancer cells exposed to ionizing radiation do not undergo immediate death even when the damage is lethal but remain within the tumour mass for some time during which they generate molecular signals that modify the cross-talk of the tumour with the host immune system. Central to this process is the activation of the DNA damage repair (DDR) response, which is often dysregulated in neoplastic cells, and associated with DNA displacement to the cytosol. The presence of dsDNA in the cytosol is sensed by the cyclic GMP-AMP synthase, cGAS, which catalyzes the formation of the second messenger cGAMP and activates STING, leading to the production of type I interferon (IFN-I). IFN-I is a critical effector of cell-mediated anti-viral and anti-tumour immunity and is primarily responsible for the recruitment and activation of BATF3-dendritic cells (DCs), and downstream activation of anti-tumour CD8 T cells. Accumulation of cytosolic IFN-stimulatory dsDNA is regulated by the single radiation dose size, with an optimal window ranging between 4-12 Gy in most human and mouse carcinoma cells tested. Above these doses, upregulation of the DNA exonuclease TREX1 results in clearance of cytosolic dsDNA, abrogating radiation immunogenicity. 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 induction of IFNRA. Furthermore, the synergy of RT with immune checkpoint blockers (ICBs) anti-CTLA-4 or anti-PD-1 and the induction of abscopal effects (i.e., immune-mediated rejection of non-irradiated synchronous tumours) are completely dependent on the ability of radiotherapy to induce cancer cell-intrinsic IFN-I (1). Tumor-derived dsDNA has also been shown to be critical for cGAS/STING- mediated production of IFN-I by DCs infiltrating immunogenic tumors (2). We have recently found that activation of DCs by tumor-derived dsDNA is modulated by RT and regulated by TREX1. Exosomes derived from irradiated cancer cells deliver the IFN-stimulatory dsDNA cargo to the cytosol of DCs, leading to their STING- mediated activation and production of IFN-I (Diamond et al., in revision). The exosome dsDNA cargo is under the control of TREX1 expressed in the parent cancer cells, indicating that the dose and fractionation used to irradiate the tumor determines immune activation in the tumor microenvironment by multiple mechanisms. These findings have critical implications for the use of radiotherapy to increase the response to ICBs, a combination currently being tested in many clinical trials. Supported by NIH 1R01CA201246 and 1R01CA198533, Breast Cancer Research Foundation, and The Chemotherapy Foundation. References 1. Vanpouille-Box, C., A. Alard, M. J. Aryankalayil, Y. Sarfraz, J. M. Diamond, R. J. Schneider, G. Inghirami, C. N. Coleman, S. C. Formenti, and S. Demaria. 2017. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun 8: 15618. 2. Woo, S. R., M. B. Fuertes, L. Corrales, S. Spranger, M. J. Furdyna, M. Y. Leung, R. Duggan, Y. Wang, G. N. Barber, K. A. Fitzgerald, M. L. Alegre, and T. F. Gajewski. 2014. STING-dependent cytosolic DNA sensing

mediates innate immune recognition of immunogenic tumors. Immunity 41: 830-842. SP-0335 Clinical data informing dose/dose per fraction and scheduling strategies D. De Ruysscher 1 1 MAASTRO Clinic, Radiation Oncology, Maastricht, The Netherlands Abstract text It is well-known that radiotherapy modulates the immune system in such a way that together with immune therapy it may provoke a local and systemic anti-cancer immune response. As there is substantial heterogeneity between patients, tumours, the micro-environment and intra- tumour-heterogeneity, it would be surprising that the radiation-immune response would not be affected by classical radiotherapy parameters such as dose, dose per fraction, dose rate, overall treatment time and the timing of radiotherapy with a certain immune therapy. Pre-clinical models may give a clue to all these questions, but as human tumours and the immune system are fundamentally different from that of rodents, a simple extrapolation from lab results to patients is inappropriate. Clinical trials remain therefore essential. To the best of my knowledge, at the time of writing, no prospective studies that specifically were designed to address dose/ fractionation questions have been published. Moreover, in the absence of established biomarkers, the only endpoints that can be used are related to clinical outcome, such as response rates, progression-free survival (PFS) and overall survival (OS). Prospective non-randomized studies that combined interferon, IL-2, GM-CSF or ipilimumab with radiotherapy ranged from a single fraction of 8 Gy to 60 Gy in 2 Gy fractions, with no clear differences in outcome. Abscopal responses were observed with radiotherapy in patients who progressed after ipilimumab and in whom IO was continued after 30 Gy/ 10 fractions, 20/5 and 24/1. In NSCLC, abscopal respons was seen after 30 Gy/ 10 fractions. In conclusion, the optimal dose/ fractionation to induce immune activation is far from being elucidated and may occur over a wide range of doses and fractionations. SP-0336 Ongoing and upcoming clinical trials evaluating different RT schedules in combination with immunotherapy F. McDonald The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust

Abstract not received

Symposium: New strategies to target hypoxia in combination with radiotherapy

SP-0337 Understanding and targeting the underlying drivers of tumor hypoxia B. Wouters 1 , D. Cojocari 2 , J. Zhang 2 , T. McKee 2 , M. Zaidi 2 , M. Koritzinksy 2 1 Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, Canada 2 Princess Margaret Cancer Centre, Princess Margaret Cancer Centre, Toronto, Canada Abstract text Low oxygenation, or hypoxia, is prevalent in human solid tumours and is a known contributor to therapy resistance. Pancreatic cancer is characterized by a poorly perfused, hypoxic microenvironment which contributes to poor treatment response and dismal patient survival