Biology and Therapy of Lymphopenia

主要活动：该项目使用小动物模型来进行有针对性的问题，以及对健康人体细胞和从经历淋巴细胞耗竭的患者获得的细胞的研究。这种从实验室到床边到实验室的方法提供了深入的见解，增加了基本的理解，并为临床应用奠定了基础。具体目标：该项目的具体目标是：1）提高对T细胞耗竭生物学的理解，2）开发新的治疗方法来改善免疫重建，或者可以复制淋巴细胞减少症的有益方面，同时避免长期的有害影响。显著结果：我们以前已经证明，年龄，疾病和治疗相关的影响胸腺功能的主要因素限制T细胞免疫重建后，淋巴细胞耗竭。我们以前也证明了免疫恢复的胸腺非依赖性途径可以在很大程度上恢复免疫能力，并在癌症免疫治疗的背景下很好地准备操纵。我们以前发现，白细胞介素-7是胸腺非依赖性免疫重建的主要驱动力，并集中精力在重组人IL-7的临床开发上。该项目在2015财年的第一个主要成就是完成了一项临床试验，其中rhIL 7被用于一线治疗后患有高风险儿科肉瘤的大型儿童和年轻人队列。这是迄今为止在儿童中使用rhIL 7的唯一临床经验。我们证明了该药物在癌症强化化疗后增加免疫重建的速度和程度方面是安全和高效的。我们还观察到，与以前报道的类似人群相比，本研究治疗的患者生存率显著提高。这些结果正在准备出版。我们还使用下一代测序进行了最先进的研究，以计数rhIL 7与非IL 7治疗的患者的T细胞受体库。这些研究证明了重组人白细胞介素-7的库的多样化，证实了先前使用分辨率低得多的方法所假设的。

Major Activities: This project uses small animal models to undertake targeted questions, as well as studies of healthy human cells and cells acquired from patients who have experienced lymphocyte depletion. This bench-to-bedside-to-bench approach provides insights that increase basic understanding and set the stage for clinical application. Specific Objectives: Specific objectives of this project are to: 1) improve understanding of the biology of T cell depletion and 2) develop new therapies to improve immune reconstitution or that could replicate the beneficial aspects of lymphopenia while avoiding long-term detrimental effects. Significant Results: We have previously demonstrated that age-, disease- and therapy-associated effects on thymic function are the primary factors limiting T cell immune reconstitution in humans following lymphocyte depletion. We also previously demonstrated that thymic-independent pathways of immune restoration can largely restore immune competence and are well poised for manipulation in the context of immunotherapy for cancer. We previously discovered that interleukin-7 is the major driver of the thymic-independent immune reconstitution and have focused efforts on clinical development of recombinant human IL-7. The first major accomplishment of this project during FY15 was completion of a clinical trial wherein rhIL7 was administered to a large cohort of children and young adults with high-risk pediatric sarcomas following front line therapy. This represents the only clinical experience with rhIL7 in children thus far. We demonstrated the agent to be safe and highly effective at increasing the pace and degree of immune reconstitution following intensive chemotherapy for cancer. We also observed significantly improved survival in patients treated on this study compared to that reported previously in a similar population. These results are being prepared for publication. We also conducted state-of-the-art studies using next generation sequencing to enumerate the T cell receptor repertoire of rhIL7 vs non-IL7 treated patients. These studies demonstrate diversification of the repertoire with recombinant human interleukin-7, confirming what was previously postulated using approaches of much lower resolution.