Imaging Tumor Associated Macrophages in Bone Sarcomas

 描述（由申请人提供）：患有恶性骨肉瘤和转移性疾病的儿童患者的总体5年生存率仅为30%。迫切需要新的预后生物标志物，可以作为新的系统治疗的目标，并帮助改善这些患者的预后。肿瘤相关巨噬细胞（TAM）是近年来发现的一种新的生物标志物，与恶性肉瘤患者的肿瘤进展和不良预后相关。目前正在开发针对TAM的新治疗药物，并开始进入临床。为了对可能受益于这些新的TAM调节疗法的患者进行分层并监测治疗反应，重要的是识别肿瘤被TAM严重浸润的患者。我们建议通过开发一种新的、立即临床适用的分子成像检测来解决这一未满足的临床需求，该检测用于选择性检测和定量儿科骨肉瘤中的TAM。这种新的成像测试依赖于铁补充剂ferumoxytol的标签外使用，ferumoxytol是一种FDA批准的氧化铁纳米颗粒化合物，被TAM吞噬。由于ferumoxytol纳米颗粒可以用磁共振成像（MRI）检测到，我们假设ferumoxytol增强的MRI可以用作骨肉瘤中TAM的立即临床适用的成像生物标志物。据我们所知，这是第一次尝试在患者中使用FDA批准的纳米颗粒可视化TAM。在一个两步的方法，我们将首先调查是否提出ferumoxytol TAM成像测试可以检测到新的免疫调节癌症治疗在小鼠模型中的反应。随后，我们将通过将ferumoxytol肿瘤MRI增强与组织病理学TAM数量和分布相关联，为儿科骨肉瘤患者提供概念证明。这种动物模型和患者研究的结合将为联合临床成像研究建立初步数据，这是美国国家癌症研究所的一项新的精准医学计划。开发TAM成像测试将代表临床医生的重大突破，作为风险分层的新手段，并作为跟踪癌症免疫治疗试验中治疗反应的金标准成像测试，包括计划于2016年在斯坦福大学进行的首次人体抗CD47免疫治疗试验。

 DESCRIPTION (provided by applicant): The overall five-year survival of pediatric patients with malignant bone sarcomas and metastatic disease is only 30%. There is an urgent need for new prognostic biomarkers, which could serve as targets for new systemic therapies and help improve outcomes for these patients. Tumor-associated macrophages (TAM) have been recently identified as novel biomarkers, which are associated with tumor progression and poor prognosis in patients with malignant sarcomas. New therapeutic drugs that target TAM are currently being developed and are starting to enter the clinic. To stratify patients who might benefit from these novel TAM- modulating therapies and to monitor treatment responses, it is important to identify patients whose tumors are heavily infiltrated with TAM. We propose to address this unmet clinical need by developing a novel and immediately clinically applicable molecular imaging test for selective detection and quantification of TAMs in pediatric bone sarcomas. This new imaging test relies on off-label use of the iron supplement ferumoxytol, an FDA-approved iron oxide nanoparticle compound, which is phagocytosed by TAM. Since ferumoxytol nanoparticles can be detected with magnetic resonance imaging (MRI), we hypothesize that ferumoxytol- enhanced MRI can be used as an immediately clinically applicable imaging biomarker for TAMs in bone sarcomas. To the best of our knowledge, this is the first attempt to visualize TAMs with FDA-approved nanoparticles in patients. In a two-step approach, we will first investigate whether the proposed ferumoxytol TAM imaging test can detect responses to new immune-modulating cancer therapies in a mouse model. Subsequently, we will provide proof of concept in pediatric patients with bone sarcomas, by correlating ferumoxytol tumor MRI enhancement with histopathological TAM quantities and distribution. This combination of studies in animal models and patients will establish preliminary data for co-clinical imaging research, a new precision medicine initiative of the National Cancer Institute. Developing a TAM imaging test would represent a significant breakthrough for clinicians as a new means for risk stratification and as a gold-standard imaging test for tracking treatment response in cancer immunotherapy trials, including a planned first-in-man anti-CD47 immunotherapy trial at Stanford University in 2016.