Normal Tissue Protection
Preventing radiation-induced normal tissue toxicity, a role for the immune system?
Host: Universiteit Maastricht
Contact person: email@example.com
Location: Maastricht, The Netherlands
Lung cancer is by far the most common thoracic malignancy worldwide. Radiation in combination with chemotherapy is currently the standard treatment for locally advanced stages, sometimes in combination with targeted agents or immunotherapy. Treatment however is often associated with high rates of radiation-induced adverse effects. Strategies to reduce the likelihood of radiation-induced tissue damage are through adherence to dose-volume constraints or the use of radioprotectors. Using a dedicated precision image-guided small animal irradiation device, we already have shown the feasibility of longitudinal CT-based monitoring of targeted upper right lung irradiation and the possibility to monitor the effects of anti-fibrotic drugs. The overall objective of this project is to understand the biology of radiosensitivity and how to exploit this for therapeutic gain by investigating what thoracic organ sub-regions are most radiosensitive using dose painting approaches, how polyphenols as caffeic acid phenethyl ester (CAPE) protect these sub-regions by elevating oxidative stress to promote anti-inflammatory and immunomodulatory effects.
This project will provide insights in the differential radiosensitivity of thoracic organ sub-regions in order to identify the areas to be spared as much as possible or the areas that can withstand a higher dose. This will enable future biology-guided radiotherapy as opposed to current clinical practice. Additionally, the protective effects of CAPE and the molecular mechanisms supporting these effects will be elucidated for the different organ sub-regions.
Targeting pathologic macrophages for widening the therapeutic window
Host: Universitätsklinikum Essen
Contact person: firstname.lastname@example.org
Location: Essen, Germany
Macrophages play a central role in tissue homeostasis, orchestration and resolution of inflammation, and tissue repair but they also support tumor growth and are suspected to promote resistance to radioimmunotherapy. These pleiotropic actions are based on the pronounced plasticity of the macrophage phenotype that differs depending on tissue/tumor type, microenvironment and treatment. We revealed that radiation-induced environmental changes in normal and tumor tissues induce monocyte/macrophage recruitment, (re)polarization and phenotypic changes towards M2-like pro-fibrotic or pro-tumorigenic phenotypes. However therapy-induced phenotypic changes as well as phenotypic similarities and differences between TAMs and fibrosis-associated macrophages require further definition if we aim to target macrophage responses to improve treatment outcome. Here we aim to define the role of macrophage plasticity (TME-induced, therapy-induced) for both, the efficacy and toxicity of radiotherapy and combined radio-immunotherapy.
Using adequate in vitro co-culture systems and in vivo tumor and normal tissue toxicity models in immunocompetent mice this project will establish spatiotemporal local and systemic changes in the macrophage molecular repertoire during the course of radiation treatment (blood, tumor, normal tissue), their impact on other immune cell types, and potential radiation-induced environmental changes driving phenotypic immune changes in tumor and normal tissues. This research will reveal response-markers and therapeutic targets for improving efficacy of radio(immuno)therapy without increasing toxicity by targeting macrophage-induced therapy escape.
Radiotherapy treatment volume and tumor immune response
Host: University of Zurich
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Location: Zurich, Switzerland
Preclinical studies with hypofractionated regimens have revealed that increased doses of ionizing radiation (IR) induce potent anti-tumor immune responses, as a result of IR-induced immunogenic tumor cell death. These insights have boosted an immense level of translational and clinical research at the interface of radiotherapy and immunology leading to promising clinical trials of radiotherapy in combination with immune checkpoint inhibitors. However, we have only limited insight on such fundamental questions how radiotherapy with larger treatment volumes will affect the immune system and subsequently the tumor immune response. Here we will investigate the impact of the radiotherapy treatment volume on the efficacy and the immune response alone and in combination with immune checkpoint inhibitors against the irradiated primary tumor and abscopal tumor burdens.
This project will, using adequate preclinical murine tumor models and a state-of-the art small animal image-guided radiotherapy platform, establish a relationship between the size of the radiotherapy treatment volume directed against the primary tumor, the immunological responses and the therapeutic outcome towards the primary but also the non-irradiated secondary tumor. This research project will therefore contribute to a better understanding and potential treatment optimization of patients in this scenario.
Molecular and cellular consequences of FLASH radiotherapy on healthy tissues and organoids
Host: Institut Curie Paris
Contact person: firstname.lastname@example.org
Location: Paris, France
Recent work from the lab and others indicates that FLASH-RT spares healthy tissue by preserving the stem/progenitor cells that allow a complete recovery after radiation injury. However, the molecular mechanisms underlying the FLASH sparing effect remains unknown. In this project, we propose, using cutting-edge technologies, to investigate the molecular and cellular consequences of FLASH compared to conventional (CONV) radiation therapy on healthy tissue.
This project will define the molecular and cellular characteristics that underlie the FLASH sparing effect using single cell RNA sequencing and spatial transcriptomic (sequential smFISH). The results will be validated in 3D cultures derived from patients and will shed some light on the inter-individual responses to FLASH radiation therapy across patients. This aspect will be of utmost importance for future FLASH clinical trials in order to recruit the patients that will benefit from FLASH radiation therapy.