ESTRO 2025 - Abstract Book

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Invited Speaker

ESTRO 2025

brachytherapy (EMBRACE II, NCT03617133). From the afore mentioned we can conclude that through several ongoing activities in preclinical research settings and clinical trials, evidence for effects of radiotherapy (including brachytherapy) in combination with immunotherapy for gynaecological cancers is slowly emerging.

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Speaker Abstracts Radiobiological general aspects Peter Hoskin Cancer Centre, Mount Vernon Hospital, Northwood, United Kingdom. Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

Abstract:

The interaction of radiation with a biological system is defined by the 6 ‘R’s each of which is relevant when considering radioimmunotherapy. Thus DNA damage mediated by both a direct and indirect effect of radiation on the helical structure resulting in single and double strand breaks which may have both lethal and sublethal effects on the cell will predominate in defining the biological consequences. The classical events following the passage of a gamma ray through the cell; repair, reoxygenation, redistribution and reoxygenation will be accompanied by reactivation of the immune response reflecting the diverse effects of radiation on the immune system. Irradiation of a tumour has been described as producing an in situ vaccine. Cellular damage and release of tumour antigens via mTOR activation to present tumour antigens will stimulate a cascade leading to activation of dendritic cells that migrate to lymph nodes, resulting in antigen presentation and subsequent tumour-specific T cell activation and proliferation. The release of DNA fragments to the cytoplasm will result in activation of the cGAS/STING pathway resulting in reactivation of both proinflammatory cytokines such as those which modulate interferon and other immune modulators and also immunosuppressive cytokines in addition to increasing inhibitory immune cells such as Treg cells and myeloid derived suppressor cells (MDSCs). Thus there is a complex interplay between radiation and the immune landscape. A characteristic of brachytherapy is the delivery of high doses per fraction in HDR or prolonged continuous radiation exposure in LDR and that the radiation distribution is inhomogeneous with high dose regions of 200% or more around the radiation source. The conformal nature of brachytherapy dose distributions will spare lymphatic channels and lymph nodes preserving lymphocyte activity. Large doses per fraction >10Gy such as those delivered in HDR brachytherapy will result not only in DNA damage and anyigen release as described above but also endothelial cell apoptosis through ceramide release from sphingomyelin. It has also been shown that biological effects are seen when there is irradiation of the cell cytoplasm and in cells which are outside the radiation dose, so called bystander effects. Other indirect effects may occur due to radiation effects on the cell membrane and mitochondria. These effects predominate at low dose rate and may explain the higher RBE of LDR brachytherapy. The complex interplay between the many facets of the immune response to cancer and the impact of radiation on it are modulated by scheduling, dose per fraction and dose rate many aspects of which are relevant to the interplay between brachytherapy and immunotherapy.