ESTRO 2021 Abstract Book

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ESTRO 2021

mechanisms that are in place once cancer is established. These immunological barriers require correction/abrogation for RT to successfully immunize the patient against her/his cancer. Importantly, the mechanisms of immune evasion of cancer have revealed to be complex and depend upon multiple variables, including tumor and tissue type-specific mechanisms, as well as host’s genetic factors, metabolism and microbiome. With regards to RT, multiple factors are emerging as relevant to potentiate its immunogenicity. They include the anatomic selection of treatment fields, lymphatic sparing, specific radiation dose and fractionation as well as optimal sequencing. For instance, in the setting of metastatic disease, cancer heterogeneity and heterogeneity of mechanisms of immune evasion across metastasis in different tissues ( De Mattos-Arruda L, et al. Cell, 2019 ) warrants the need for radiation to target all detectable metastatic deposits. A multi- institutional Canadian trial on oligometastatic cancer patients (with up to 5 metastases) has demonstrated a promising improvement in time-to-progression and survival after stereotactic body radiotherapy (SBRT) to each metastasis ( Palma DA et al, Lancet, 2019 ), when compared to best supportive care. In addition to targeting heterogeneity, maximal reduction of tumor burden by multi-site SBRT can enable an immunological equilibrium, and potentially prolong survival. Conversely, preclinical evidence discourages the inclusion of draining nodal stations in the field of radiotherapy, when RT is used in combination with immunotherapy strategies ( Marciscano A et al, Clin Cancer Res; 2018). Finally, preclinical and clinical evidence supports the use of focal hypo-fractionated regimens, that minimally impact the viability of circulating immune cells. While ongoing translational and clinical research is testing radiation immunogenicity with current immunotherapy, it is also relevant to investigate how to best enact the immunogenic effects of radiotherapy wen used in combination with standard systemic cancer therapies. Most standard cancer therapies also have relevant effects on the immune system (for example see Ameratunga M et al, Clin Cancer Res 2019 ): deciphering the immunological effects that accompany the cytocidal effects of available cancer therapies can guide their optimal integration. In this regard, it is important to define the optimal timing of integration of RT with systemic therapy. An example comes from preclinical results of different sequencing of focal radiation with with CDK4/6 inhibitors and endocrine therapy in a murine model of ER+ breast cancer will ( Petroni G. et al, Clinical Cancer Research, 2021) . As more mechanisms of cancer immune evasion continue to emerge from preclinical and clinical research, radiation is establishing its new role as a powerful adjuvant to immunotherapy. Abstract Text In this introductory presentation, I will focus on the following aspects showing the importance of normal tissue models: 1. when moving from promising molecular-based therapies to the clinic we first need insight in the in vivo modulation of tissue physiology (e.g., microvascular, stem cell niches and kinetics) 2. with the increased precision of RT treatments we also need more realistic normal tissue models, especially partial volume irradiations now possible with small animal platforms or other high precision proton or carbon beams 3. with SBRT and extreme hypofractionation with strongly reduced overall times there is a paradigm shift in the fact that early effects in epithelial tissues are becoming dose limiting rather than the focus on late effects in the (almost) past era of hyperfractionation and low alpha/beta values. SP-0238 Normal tissue effects of radiation combined with vascular targeting agents M. Horsman 1 1 Aarhus University Hospital, Experimental Clinical Oncology-Dept. Oncology, Aarhus N, Denmark Abstract Text There is a clear dose response relationship between the dose delivered to tumors and their response to radiation. Unfortunately, there is also an increase in normal tissue damage with increasing radiation dose and it is this complication that limits the total radiation dose that can be given. Substantial effort has been made to try and preferentially modify tumor radiation response and so increase the separation between the tumor and normal tissue dose response curves. This may be possible using agents that specifically target tumor vasculature. The tumor vascular supply is critical for the growth and development of solid tumors and this significance has made it an excellent target using so called vascular targeting agents (VTAs). There are two categories of VTAs. These are angiogenesis inhibitors (AIs) which prevent the process through which the tumor vasculature develops from the host blood vessels, or vascular disrupting agents (VDAs) that damage the already establish tumor vasculature. While numerous pre-clinical, and even clinical, studies have shown that both types of VTAs can be applied to improve tumor response to radiation, very few studies have investigated the combination of VTAs with radiation in normal tissues. This is primarily because of the assumption that since VTAs preferentially target tumors and not normal tissues one is unlikely see any interaction with SP-0236 New PET technologies for the imaging of immune responses TBC Abstract not available Symposium: Normal tissue effects of combined therapies SP-0237 Necessity of normal tissue models A. van der Kogel 1 1 University of Wisconsin, Human Oncology, Madison, USA