ESTRO 2023 - Abstract Book

S138

Saturday 13 May

ESTRO 2023

the tumour microenvironment (TME) can become hostile to anti-tumour immune cells which hampers the effectiveness of therapies such as immune checkpoint blockade (ICB). This has prompted the exploration of combination therapies to reshape the TME to facilitate detection and killing of cancer cells. Radiotherapy has, in pre-clinical models and in some clinical trials, shown synergy with ICB in improving local tumour control and inducing immune-mediated abscopal effects. However, recent results from clinical trials assessing radiotherapy combinations with ICB have failed to show therapeutic benefit and have dampened the initial optimism. There is an ongoing debate about target lesion selection, radiation target volume, dose, and fractionation, elective nodal irradiation, as well as sequencing of radiotherapy and ICB. These are all important questions for optimizing treatment synergy. However, it is crucial to also determine how these factors impact the tumour microenvironment, the anti-tumour immune response, and the emergence of acquired therapy resistance. The stimulatory effects of radiotherapy have been well characterised, including upregulation of tumour antigen expression and presentation, induction of immunogenic cell death and activation of viral defence pathways, recruitment and activation of dendritic cells, and ultimately priming of tumour-specific T cell responses. However, the immunosuppressive aspects of radiotherapy in solid tumours (radiation-induced immune checkpoints) are less well understood. These include production of immunosuppressive cytokines, recruitment/polarisation of regulatory immune cells, and upregulation of enzymes that convert pro-immunogenic signals of radiotherapy into immunoregulatory mediators. The nucleotides ATP and NAD+ are central mediators of cellular metabolism and energy transfer. However, when they are released into the extracellular space from stressed and dying cells, they act as pro-immunogenic danger signals and regulators of tissue homeostasis, primarily via the P2X7 receptor. Radiotherapy promotes the extracellular release of ATP and NAD+ but also modulates the expression of key enzymes that catabolize these molecules resulting in immune resistance. Firstly, radiation induces upregulation of tumour-expressed ectonucleotides, including CD73, which hydrolyse extracellular ATP and NAD+ resulting in accumulation of immunosuppressive adenosine in the tumour microenvironment. Secondly, radiation upregulates tumour expression of the mono-ADP-ribosyltransferase ART1, which utilizes free NAD+ to mono-ADP- ribosylate the P2X7 receptor on CD8 T cells and DCs triggering their elimination by NAD-induced cell death. Our recent work has shown that targeting CD73 and ART1 with therapeutic antibodies, reversed radiation-induced immune resistance promoting tumour infiltration of DCs and augmented CD8 T cell responses in mouse models of lung and mammary carcinoma. In summary, improved understanding of the balance between immunogenic and suppressive effects of radiotherapy will allow for identification of biomarkers of response and novel targets that can offset radiation-induced immune checkpoints. This will inform the design of rational clinical trials of radiotherapy/immunotherapy combinations which will ultimately help patients with advanced cancer. SP-0190 Improving radiotherapy-induced immune stimulation by DNA damage response inhibition K. Harrington 1 1 The Institute of Cancer Research, Division of Radiotherapy and Oncology, LONDON, United Kingdom Abstract Text Repair of radiation-induced DNA damage is one of the 5 Rs of radiobiology and, in recent years, has been the subject of intense fundamental and translational research activity. Cancer cells frequently acquire a state of genomic instability, through mutational and non-mutational alterations in DNA repair pathways, as a means of driving clonal evolution and therapy resistance. While this state is associated with poor outcomes for patients, it also represents a therapeutic opportunity for oncologists who seek to exploit specific synthetically-lethal vulnerabilities in cancer cells with aberrant DNA repair capacity. In this presentation, the basis of specific synthetically-lethal therapeutic strategies will be introduced and reviewed. At first, attempts to target cancer-specific vulnerabilities in combination with radiotherapy focused on the concept of tumour cell-specific radiosensitisation through the addition of small-molecule inhibitors with sensitisation enhancement ratios (SER) ranging between >1 and approximately 4. More recently, however, there has been a growing realisation that molecular radiosensitisation can also be associated with increased immune activation within the tumour microenvironment, and this might not necessarily require maximal exploitation of high-SER radiosensitisation. The pathway involving ataxia telangiectasia and Rad3-related (ATR) kinase represents an excellent candidate for therapeutic exploitation. In this presentation, data on the true radiosensitising effects of ATR inhibition will be discussed. Subsequently, the pro-inflammatory effects of radiotherapy plus ATRi will be reviewed, focusing on published and unpublished data from preclinical studies of combinations with immune checkpoint blockade (anti-PD-L1, anti-TIGIT and anti-NKG2A antibodies). In addition, unpublished data on the immune effects of ATR inhibition (with ceralasertib, AZD6738) from our completed clinical PATRIOT trial will be presented.

Joint Symposium: ESTRO-CARO: Next generation radiation oncology - How to best obtain evidence for emerging technologies

SP-0191 Methodological issues related to evaluating personalised radiotherapy E. Hall 1 1 Institute of Cancer Research, Clinical Trials and Statistics Uni, London, United Kingdom

Abstract Text Personalised radiotherapy is a term that can be used to describe how the radiation dose, fractionation, target volume, margins and/or the use of concomitant systemic treatment or radiosensitising agents might be individualised based on knowledge of tumour biology or patient characteristics. The aim of tailoring radiotherapy in such a way, or of prospectively adapting individual treatment plans based on biomarkers of response or normal tissue effects, is to improve the therapeutic ratio through improved disease control and/or reduced side effects. Methodology for the clinical evaluation of personalised radiotherapy hinges on the magnitude of the potential benefits in either (or both) of these domains and of the proportion of patients receiving personalised treatment. Strategies that result in minor changes to the treatment plan for a very small numbers of patients may not lead to cost effective benefit at a population level. Where personalisation is hypothesised to lead to moderate benefits, randomised controlled trials utilising reliable and patient prioritised endpoints are needed drive practice change; where large and low