Project 2: Radiation-Induced Lymphopenia: Understanding, Predictive Modeling and Developing Photon and Proton-Based Mitigation Strategies.

项目 2 - 摘要 辐射引起的淋巴细胞减少症：理解、预测建模和开发光子和 基于质子的缓解策略 越来越多的证据表明，辐射诱发的淋巴细胞减少症 (RIL) 与多种癌症有关 常见，但常常被视为不可避免的副作用而被忽视。严重 RIL 已被证明与 疾病特异性结果不佳。在实体瘤的治疗中广泛使用放射治疗（RT） 肿瘤需要开发 RIL 缓解策略。我们有令人信服的证据表明 质子疗法 (PT) 与光子（或 X 射线）疗法 (XRT) 的淋巴细胞保留效果的差异， 推测归因于它们的剂量分布模式的差异。我们的工作进一步 证明患者特异性因素和剂量因素都会导致严重 RIL 和 T 细胞的风险 克隆性。我们的假设如下： (1) 考虑个体患者的 RIL 预测模型 敏感性和剂量因素将具有临床显着的预测能力； (2) 减少剂量 处于危险中的循环免疫细胞和免疫结构不仅保留了数量，而且更重要的是， 淋巴细胞的质量，对癌症免疫和疾病结果有直接的积极影响； (3) 通过利用强度调制质子和光子 RT（IMPT 和 IMRT），采用个性化 从模型得出的剂量限制，我们将能够选择最佳的治疗方式 （质子或光子）并制定针对患者的特定策略，以大幅减轻 RIL 及其后果。 为了检验这些假设，我们提出了三个具体目标。在目标 1 中，我们将利用我们的大型数据库 主要针对食管癌、肝癌和脑癌患者，以提高我们对淋巴细胞耗竭作为一种治疗方法的认识 剂量测定和患者特异性基线临床因素的函数，并开发模型来准确预测 个性化严重 RIL 风险。在目标 2 中，我们将评估放射治疗方式的临床影响 T 细胞多样性、免疫库和功能性免疫状态。我们将检验以下假设： RT 后通过免疫表型、T 细胞多样性和功能免疫来测量淋巴细胞的质量 是临床结果的主要驱动因素，而不仅仅是绝对淋巴细胞计数。在目标 3 中，我们将评估 使用独立的回顾性和前瞻性数据来验证我们模型的有效性。我们还将应用模型 为特定患者选择最佳治疗方式和技术，并制定个性化治疗方案 用于优化质子和光子辐射剂量分布模式的剂量测定约束，以最大限度地减少 RIL 严重性和风险。当这个项目完成后，我们将更好地了解如何 基线临床特征以及质子和光子剂量测定因素影响 RIL 风险和严重程度，T 细胞 多样性和功能性免疫。此外，我们将开发先进的质子和光子剂量测定法 降低 RIL 风险的策略。我们的研究有可能更好地为每种情况选择最佳模式 患者，优化 IMPT 和 IMRT 治疗，最大限度地减轻淋巴细胞减少症，从而改善 RT 结果， 并在未来将放疗与免疫治疗策略进行最佳整合。

Project 2 - Summary Radiation-Induced Lymphopenia: Understanding, Predictive Modeling and Developing Photon and Proton-Based Mitigation Strategies There is accumulating evidence across many types of cancers that radiation-induced lymphopenia (RIL) is common, but it is often ignored as an unavoidable side effect. Severe RIL has been shown to correlate with poor disease-specific outcomes. Extensive use of radiotherapy (RT) in the curative management of solid tumors necessitates the development of RIL-mitigation strategies. We have compelling evidence of significant differences in the lymphocyte-sparing effects of proton therapy (PT) vs. photon (or x-ray) therapy (XRT), presumably attributable to the differences in their dose distribution patterns. Our work has further demonstrated that both patient-specific and dosimetric factors contribute to the risk of severe RIL and T-cell clonality. Our hypotheses are as follows: (1) RIL predictive models that account for individual patient susceptibilities and dosimetric factors will have clinically significant predictive power; (2) reducing dose to circulating immune cells and immune structures at risk preserves not only the quantity but, more importantly, the quality of lymphocytes, which has a direct positive impact on cancer immunity and disease outcomes; (3) through the utilization of intensity-modulated proton and photon RT (IMPT and IMRT), employing individualized dosimetric constraints derived from the models, we will be able to select the optimum treatment modality (protons or photons) and develop patient-specific strategies to substantially mitigate RIL and its consequences. To test these hypotheses, we propose three specific aims. In Aim 1, we will utilize our large databases of mainly esophagus, liver and brain cancer patients to improve our understanding of lymphocyte depletion as a function of dosimetric and patient-specific baseline clinical factors and develop models to accurately predict individualized severe RIL risk. In Aim 2, we will evaluate the clinical impact of the radiation treatment modality on T-cell diversity, immune repertoire, and functional immune status. We will test the hypothesis that the quality of lymphocytes as measured by immune phenotyping, T-cell diversity, and functional immunity after RT is a major driver of clinical outcomes rather than just the absolute lymphocyte count. In Aim 3, we will assess the validity of our models using independent retrospective and prospective data. We will also apply the models to select the optimum treatment modality and technique for a given patient and define the personalized dosimetric constraints to be used to optimize proton and photon radiation dose distribution patterns to minimize RIL severity and risk. Upon the completion of this project, we will have a better understanding of how the baseline clinical characteristics and proton and photon dosimetric factors impact RIL risk and severity, T-cell diversity, and functional immunity. Moreover, we will have developed advanced proton and photon dosimetric strategies to reduce RIL risk. Our research has the potential to better select the optimum modality for each patient, to optimize IMPT and IMRT treatments to maximally mitigate lymphopenia to improve RT outcomes, and to optimally integrate RT with immunotherapy strategies in the future.