Project 3: Carbon and Electron FLASH radiotherapy for mitigation of normal lung injury in NSCLC

项目3 胸部放疗的晚期毒性限制了肺癌的治愈性治疗，并影响了长期生活质量。 放射诱导的肺纤维化（RILF）是风险器官（OAR）模型的范例之一， 电子闪光辐射的后期毒性的大幅减少被成功地证明。此外，委员会认为， 已经假定生理氧条件控制正常组织中的FLASH保护作用 而相对低氧的肿瘤显示出相似的敏感性水平。唯一可能提供超高 剂量率FLASH照射治疗胸部深部恶性肿瘤将利用粒子。因此本 一个项目旨在提供证据，如果碳，质子和电子闪光将节省OAR（肺，血管，心脏 和食管），同时证明在 局部控制非小细胞肺癌（NSCLC）肿瘤。全胸照射（WTI） 和联络 辐照 用碳离子、质子和电子（参考粒子）FLASH与S-PRT进行。的 FLASH对纤维化肺组织微血管损伤及M2极化炎症反应影响 以及现场心脏和GI毒性（食道）。减少高浓度的氧依赖性 LET碳离子FLASH可以进一步用于探索短暂缺氧对 Flash效应的出现。除了用碳离子进行LET调制之外，进一步开发超- O2的快速光学传感器被设想用于在线监测、证明或反驳假设 氧依赖 的FLASH 体外和体内作用。基于胸部挽救性再照射的应用日益增多， 恶性肿瘤，FLASH在暴露于初始分级WTI后保留OAR毒性方面的影响将是 组织辐射记忆的替代物，即分子以及衰老细胞样表型 开关将以单个单元分辨率去卷积。考虑到在病理生理学上的潜在差异， FLASH，TGF β，CTGF和内皮抑素作为RILF减轻FLASH效应的关键参与者的相关性将 被评价。在肿瘤控制的背景下，肿瘤内氧合异质性对FLASH的影响 将研究效果。假设与正常组织类似，灌注良好的肿瘤区域可以通过 FLASH，证明F-与S-PRT相比在肿瘤生长抑制方面的非劣效性将具有极其重要的意义 用于FLASH的临床翻译。除OER效应外，肿瘤间异质性对F-PRT的影响 将通过研究相关途径阐明疗效 参与ROS稳态 使肿瘤抵抗 NSCLC患者的S-RT。LET和氧分压对FLASH效应的相关性有待进一步研究 在3D体外肿瘤模型和微血管类器官中进行了系统研究。根据初步数据， 干扰素信号可能是 差异影响 通过FLASH，细胞溶质cGas/STING/IFN的级联反应 检查激活及其在与免疫- 检查点阻断作为最近批准的NSCLC标准方案，将进行评价。

Summary Project 3 Late toxicity of thoracic irradiation limits curative treatment of lung cancer and compromises long-term life quality. Radiation induced lung fibrosis (RILF) is among the paradigm organs at risk (OAR) models for which evidence for substantial reduction in late toxicity of electron FLASH irradiation was successfully demonstrated. Moreover, the physiological oxygen condition has been postulated to govern the FLASH protective effect in normal tissues while relatively hypoxic tumors demonstrate similar level of sensitivity. The only possibility to provide ultra-high dose rate FLASH irradiation for deep-seated thoracic malignancies will be to utilize particles. Therefore, this project aims to provide evidence if Carbon-, Proton- and Electron FLASH will spare OAR (lung, vascular, heart and esophagus) following thoracic irradiation from early/late toxicities while demonstrating non-inferiority in terms of local control of non-small cell lung cancer (NSCLC) tumors. Whole thoracic irradiation (WTI) and focal irradiation are performed with carbon ions, protons and electron (reference particle) FLASH vs. S-PRT. The impact of FLASH on lung microvascular damage and M2 polarized inflammatory response in fibrotic lung tissue as well as in-field heart- and GI-toxicity (esophagus) will be examined. Reduced oxygen dependence of high- LET carbon ion FLASH could be further instrumental in exploration of the impact of transient hypoxia for the emergence of FLASH effect. In addition to LET modulation with carbon ions, further development of an ultra- rapid optical sensor for O2 is envisioned to online monitor, prove or disprove the postulated oxygen dependence of FLASH effect in-vitro and in-vivo. Based on increasing application of salvage reirradiation of thoracic malignancies, the impact of FLASH in sparing OAR toxicity post exposure to initial fractionated WTI will be studied and surrogates of tissue radiation memory, i.e. molecular as well as senescent-cells like phenotypic switches will be deconvoluted at single cell resolution. Considering potential differences in pathophysiology of FLASH, the relevance of TGFbeta, CTGF and endostatin as key players of RILF in mitigating FLASH effects will be evaluated. In context of tumor control, the consequence of intratumoral oxygenation heterogeneity on FLASH effect will be studied. Assuming that in analogy to normal tissue, well perfused tumor regions may be spared by FLASH, demonstration of non-inferiority of F- vs. S-PRT in tumor growth inhibition will be of utmost significance for clinical translation of FLASH. In addition to OER effect, implication of intertumoral heterogeneity on F-PRT efficacy will be elucidated by studying relevant pathways involved in ROS homeostasis rendering tumor resistant to S-RT in NSCLC patients. The relevance of LET and partial oxygen pressure on FLASH effect will be further systematically studied in 3D in-vitro tumor models and microvascular organoids. Based on preliminary data that interferon signaling might be differentially affected by FLASH, the cascade of cytosolic cGas/STING/IFN activation is examined and its potential consequence for inferior outcome in combination strategies with immune- check-point blockade, as recently approved standard regimen for NSCLC, will be evaluated.