Biology and Therapy of Lymphopenia

主要活动：该项目使用小动物模型进行有针对性的问题，以及对健康的人类细胞和从经历过淋巴细胞枯竭的患者那里获得的细胞进行研究。这种床到床的方法提供了洞察力，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细胞耗竭生物学的了解，2)开发新的治疗方法，以改善免疫重建，或能够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。重要结果：我们先前已经证明，年龄、疾病和治疗对胸腺功能的相关影响是限制淋巴细胞耗尽后人类T细胞免疫重建的主要因素。我们以前也证明了胸腺不依赖的免疫恢复途径可以在很大程度上恢复免疫功能，并为在癌症免疫治疗的背景下进行操纵做好准备。我们先前发现IL-7是胸腺非依赖性免疫重建的主要驱动力，并将精力集中在重组人IL-7的临床开发上。该项目在2015财年的第一个主要成果是完成了一项临床试验，在该试验中，在一线治疗后，对大量患有高危儿童肉瘤的儿童和年轻人进行了rhIL7治疗。这是迄今为止在儿童中使用重组人白细胞介素7的唯一临床经验。我们证明，该制剂在癌症强化化疗后提高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，与之前在类似人群中报道的相比，接受这项研究的患者的存活率显著提高。这些结果正在准备出版。我们还进行了最先进的研究，使用下一代测序来列举重组人白介素7与非白介素7治疗患者的T细胞受体谱系。这些研究证明了重组人白介素7的全谱多样化，证实了以前使用分辨率低得多的方法所作的假设。

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.