Immunobiology of Pediatric Tumors

我们以前已经证明尤文氏肉瘤对肿瘤细胞的增殖非常敏感， 凋亡通过TRAIL受体激动剂。绝大多数尤因肉瘤细胞系表达 TRAIL-受体2（TR 2）和大多数细胞在TR 2连接的24小时内经历凋亡 受体与单克隆抗体或天然TRAIL配体。此外，异种移植 模型显示抗TR 2是抗体内生长的尤文氏肉瘤的活性剂。On this 在此基础上，我们已经启动了一项在儿童实体瘤中进行抗TR 2的I期临床试验， 目前正在审理此案。尽管有这些有希望的临床前数据，我们也 注意到少数尤文氏肿瘤细胞系对抗TR 2不敏感，我们观察到 抗TR 2不能治愈大多数具有已建立的尤因异种移植物的动物。因此，我们认为， 我们试图了解限制尤文肉瘤对TR 2敏感性的因素 目标代理人在这项工作的背景下，重要的是要注意，基于TRAIL的杀戮 是免疫系统根除肿瘤的主要途径之一， 我们对该系统的兴趣是基于直接临床应用的可能性 以及通过TRAIL受体优化细胞死亡的可能性 信号传导还可以提高针对这些肿瘤的基于免疫的疗法的有效性。的 该项目在2008财年的主要成就是出版了一份手稿 证实了半胱天冬酶8在致敏尤文肉瘤细胞中的重要性， 细胞死亡，并鉴定尤文肉瘤临床样品中caspase 8的表达， 异质的（Lissat等人，Am J Path 2007; 170：1917）。这是一项合作工作，我们 一个项目提供了50多个尤因肿瘤的半胱天冬酶8分析 这是本报告的一个基本要素。因此，我们已经证明， TRAIL介导的尤文肉瘤杀伤的全部益处，无论是通过单克隆抗体还是通过 一种溶细胞的细胞，只有在保证半胱天冬酶8表达的情况下才能完成。我们进一步 表明干扰素γ是半胱天冬酶8表达的主要调节因子， 尤文氏肉瘤细胞暴露于干扰素γ导致大量半胱天冬酶8 上调和对抗TRAIL受体疗法的敏感性增加。因此，我们将 寻求将干扰素纳入我们正在进行的抗TR 2临床试验，并将寻求 将基于联合收割机的TRAIL疗法与可将干扰素局部递送至肿瘤细胞的免疫疗法结合， 肿瘤部位，并因此潜在地彼此协同。

We have previously demonstrated that Ewings sarcomas are exquisitively sensitive to apoptosis via TRAIL receptor agonists. The vast majority of Ewings sarcoma cell lines express TRAIL-Receptor 2 (TR2) and most cells undergo apoptosis within 24 hours of ligation of the TR2 receptor with either monoclonal antibody or the natural TRAIL ligand. Moreover, xenograft models show that anti-TR2 is an active agent against Ewings sarcomas growing in vivo. On this basis, we have initiated a Phase I clinical trial of anti-TR2 in childhood solid tumors and this trial is currently proceeding. Despite this promising preclinical data, we have also noted that a minority of Ewings tumor cell lines are not sensitive to anti-TR2 and we observed that anti-TR2 was unable to cure most animals with established Ewings xenografts. Therefore, we have sought to understand the factors that limit sensitivity of Ewings sarcoma to TR2 targeted agents. It is important to note in the context of this work, that TRAIL based killing is one of the primary pathways through which the immune system eradicates tumors and therefore our interest in this system is based both upon the possibility for direct clinical application with anti-TR2 as well as the possibility that optimizing cell death via TRAIL receptor signaling could also improve the effectiveness of immune based therapies for these tumors. The primary accomplishment for this project during FY2008 was the publication of a manuscript demonstrating the importance of caspase 8 in sensitizing Ewings sarcoma cells TRAIL mediated cell death and identifying that caspase 8 expression in Ewings sarcoma clinical samples is heterogeneous (Lissat et al, Am J Path 2007; 170:1917). This was a collaborative work and our program contributed by providing the analysis of more than 50 Ewings tumors for caspase 8 expression which was a fundamental element of this report. Thus, we have demonstrated that the full benefit of TRAIL mediated killing in Ewings sarcoma, whether delivered via a moAb or via a cytolytic cell, can only be accomplished if caspase 8 expression is assured. We have further demonstrated that interferon gamma is a primary regulator of caspase 8 expression and that exposure of Ewings sarcoma cells to interferon gamma results in substantial caspase 8 upregulation and increased sensitivity to anti-TRAIL receptor therapies. We therefore will seek to incorporate interferon into our ongoing clinical trial of anti-TR2 and will seek to combine TRAIL based therapies with immune therapies that can deliver interferon locally to the tumor site and therefore potentially synergize with each other.