Mitigating High Grade Radiation-Induced Lymphopenia through Pretreatment Autologous Lymphocyte Infusion

项目总结 放射性淋巴细胞减少症(RIL)是一种常见的与辐射相关的毒性，已被认识到多年。 一个世纪，但经常被忽视，因为临床上无关紧要。然而，越来越多的证据表明， 高级别RIL(见于30-50%的患者)与预后不良密切相关。无处不在的角色 实体肿瘤治疗中的放射治疗支持开发缓解策略的需要， 尤其是对于具有发展为4级(G4)RIL的高风险的患者。我们有令人信服的证据来自 严重的RIL影响癌症控制和治疗效果的临床和临床前工作，以及 降低RIL的方法可能会改善治疗结果。以进一步开发这些方法用于临床 翻译，我们提出了两个具体目标。在目标1中，我们将建立对G4 RIL的初始预测模型 并利用我们已完成放化疗(CRT)的食道癌患者的大型数据库 为G4 RIL开发更好的预测模型，以便我们能够快速高效地识别最高风险 患者的缓解策略。在目标2中，我们将确定提高基线的可行性和安全性 启动CRT前通过自体淋巴细胞输注(ALI)检测淋巴细胞水平。从根本上说，这 研究将使我们能够开发必要的计算工具，能够在 发展严重RIL的风险，并完成使用ALI作为一种提高 治疗前的基线淋巴细胞水平，以便发生G4 RIL的可能性可能 缩减了。通过针对高危患者接受RIL缓解策略，我们将有望能够 改善标准癌症疗法的癌症结局，并建立在现有创新战略的基础上 免疫疗法和放射联合疗法。

PROJECT SUMMARY Radiation induced lymphopenia (RIL) is a common radiation-related toxicity that has been recognized for over a century but often ignored as clinically inconsequential. However, accumulating evidence has demonstrated strong association of high grade RIL (seen in 30-50% of patients) with poor prognosis. The pervasive role of radiotherapy in the curative management of solid tumors supports the need to develop mitigating strategies, particularly for patients with a high risk of developing grade 4 (G4) RIL. We have compelling evidence from both clinical and preclinical work that severe RIL impacts cancer control and therapy effectiveness, and methods to reduce RIL may improve treatment outcomes. To further develop these approaches for clinical translation, we have proposed 2 specific aims. In aim 1, we will build on our initial prediction model for G4 RIL and leverage our large database of esophageal cancer patients who have completed chemoradiation (CRT) to develop a better predictive model for G4 RIL so that we can rapidly and efficiently identify the highest risk patients for mitigating strategies. In aim 2, we will determine the feasibility and safety of raising the baseline lymphocyte levels by autologous lymphocyte infusion (ALI) prior to initiating CRT. Fundamentally, this research will allow us to develop the necessary computational tool capable of properly identifying patients at risk for developing severe RIL, and complete a small feasibility and safety study of using ALI as a way to raise the baseline pre-treatment lymphocyte levels so that the probability of developing G4 RIL could be possibly curtailed. By targeting the at-risk patients to receive RIL mitigating strategies, we will hopefully be able to improve the cancer outcomes of standard cancer therapies, and build on current innovative strategies of immunotherapy and radiation combinations.