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

项目摘要3 胸部放射治疗的晚期毒性限制了肺癌的治疗，影响了患者的长期生活质量。 放射性肺纤维化(RILF)是典型的危险器官(OAR)模型之一，有证据表明 为了大幅度降低电子闪光照射的后期毒性，已经成功地证明了这一点。此外， 生理性的氧气条件被认为控制着正常组织的闪光保护效果 而相对低氧的肿瘤表现出类似的敏感性水平。唯一的可能性是提供超高的 剂量率闪光照射对胸部深部恶性肿瘤的治疗将采用颗粒剂。因此，这 该项目旨在提供证据，证明碳、质子和电子闪光是否会使OAR(肺、血管、心脏) 和食道)在胸部照射后的早期/晚期毒性，同时显示出非劣势 非小细胞肺癌(NSCLC)肿瘤的局部控制。全胸照射(WTI) 和焦点 辐照区 使用碳离子、质子和电子(参考粒子)闪光VS S-PRT。这个 闪光对纤维化肺组织微血管损伤及M2极化炎症反应的影响 以及现场心脏和胃肠道毒性(食道)将进行检查。减少对氧气的依赖 让碳离子闪光可以进一步有助于探索短暂低氧对 闪光效果的出现。除了用碳离子调制外，进一步开发了一种超 氧气快速光学传感器有望在线监测、证明或反驳这一假设 氧依赖 闪存的 体外和体内的作用。基于救治胸部再照射应用的增加 恶性肿瘤，闪光对暴露于初始分级WTI后的桨毒性的影响将是 组织辐射记忆的研究和替代，即分子和衰老细胞样表型 开关将以单单元分辨率进行去卷积。考虑到在病理生理上的潜在差异 闪光，TGFbeta、CTGF和Endostatin作为RILF在缓解闪光效应中的关键角色的相关性将 被评估。在肿瘤控制的背景下，肿瘤内氧合不均匀对闪光的影响 我们会研究这方面的影响。假设与正常组织类似，充分灌流的肿瘤区域可以通过 Flash，展示F-PrT与S-PrT在抑制肿瘤生长方面的非劣势将具有极其重要的意义 用于临床翻译闪光灯。除OER效应外，肿瘤间异质性对F-PRT的影响 疗效将通过研究相关途径来阐明。 参与ROS动态平衡 使肿瘤产生抗药性 对非小细胞肺癌患者S-RT的影响。LET和分氧压对闪光效应的相关性将进一步提高 系统地研究了3D体外肿瘤模型和微血管器官。根据初步数据， 干扰素信号可能是 受不同影响 通过闪光，胞内cGAS/STING/干扰素的级联 研究了激活及其对免疫-免疫联合策略不良结果的潜在后果。 检查点封锁，作为最近批准的非小细胞肺癌标准方案，将得到评估。

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.