Georgetown University Lombardi Comprehensive Cancer Center Support Grant

本申请是为回应特别利益通知(NOSI)而提出的，该通知被确认为非- CA-21-083。 近年来，放射治疗(RT)已与免疫检查点抑制剂(ICIS)等药物联合应用 免疫调节剂在增强免疫介导的抗肿瘤效应及多重临床应用中的作用 目前正在进行试验，以测试这种组合。然而，在设计这些试验时，RT的剂量，分次， 关于RT、免疫刺激和免疫抑制潜力的免疫治疗的时间表 不考虑会导致应答或抵抗的RT。此外，肿瘤状态的影响， “冷”与“热”对RT介导的免疫应答的影响及RT对正常人免疫细胞的影响 组织没有得到充分的处理。然而，不同的RT方案将起到不同的作用 免疫调节药物，产生不同的免疫反应。因此，迫切需要发展 免疫辐射反应指示器(IRRI)将考虑所有这些因素，从而允许 知情的临床试验设计，以最大限度地提高收益并降低患者的风险，尤其是在 使用每组分高剂量的低分馏。 在此基础上，我们假设特定的RT特性将影响本征辐射 正常组织和TME中不同类型免疫细胞的敏感性，导致不同的免疫调节 影响，从而改变免疫反应。为了验证这一假设，我们提出了以下两个具体的假设 目的：1)确定不同细胞类型的免疫隔室的本征辐射敏感性。 正常组织和肿瘤组织对不同的辐射剂量和分割计划；2)产生IRRI后 目标1中的数据分析。 RT可通过多种机制引起显著的免疫调节，例如通过改变抗原 呈现和免疫原性细胞杀伤。根据剂量和分割的不同，RT可以增强免疫力 激活或引起免疫抑制。因此，需要开发基于肿瘤的IRRI TME和正常组织中免疫细胞的特性及其对免疫细胞的影响有助于RT的选择 诱导免疫刺激作用的养生法。这项研究的结果将有助于理解 辐射特性对TME和正常组织免疫调节的影响 明确的IRRI，将有助于为未来联合RT+临床试验的设计提供信息 免疫疗法。

This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-21-083. Recently, radiation therapy (RT) has been combined with immune checkpoint inhibitors (ICIs) and other immunomodulatory agents in an effort to enhance the immune-mediated anti-tumor effects and multiple clinical trials are ongoing to test this combination. However, while designing these trials, dose of RT, fractionation, scheduling of the immunotherapy with respect to RT, the immunostimulatory and immunosuppressive potential of RT that would either lead to response or resistance are not considered. Moreover, influence of status of tumor, whether “cold” or “hot” on RT-mediated immune response and effect of RT on the immune cells in the normal tissues are not adequately addressed. However, different RT regimens would serve as distinct immunomodulatory ‘drugs’, generating diverse immune responses. Therefore, there is an urgent need to develop an immune radiation response indicator (iRRi) that will consider all these factors and thereby would allow an informed clinical trial design to maximize benefit and reduce the risk to patients, especially when hypofractionation with high doses per fraction are used. Based on the above, we hypothesize that specific RT characteristics will influence the intrinsic radiation sensitivity of various types of immune cells in normal tissues and the TME, leading to distinct immune modulatory effects, thereby altering the immune response. To test this hypothesis, we propose the following two Specific Aims: 1) To determine the intrinsic radiation sensitivity of different cell types of the immune compartment from normal and tumor tissues to various radiation doses and fractionation schedules; 2) To generate an iRRi after analysis of data in aim 1. RT can cause significant immunomodulation via multiple mechanisms such as by altering antigen presentation and immunogenic cell killing. Depending on the dose and fractionation, RT can augment immune activation or cause immune suppression. Hence, there is a need to develop an iRRi that based on the tumor characteristics and effects on immune cells in the TME and normal tissues would help in selection of a RT regimen that induces immune stimulatory effects. The results from this study will help in understanding the influence of radiation characteristics on immunomodulation of the TME and normal tissues and will generate a definitive iRRi that will be helpful in informing the design of future clinical trials on combined RT plus immunotherapy.