Developmentally regulated antigens for immunologic targeting of pediatric brain tumors

项目总结/摘要： 脑肿瘤是儿童癌症相关死亡的头号原因。髓母细胞瘤（MB）是 最常见的恶性小儿脑肿瘤，而脑干神经胶质瘤（BSG）是最致命的。虽然 许多临床前和临床研究已经证明了免疫疗法在以下疾病中的潜在治疗益处： 实体瘤、恶性脑肿瘤仍然普遍致命。作为回应，我们的团队开创了一种 依赖于肿瘤反应性T细胞转移的细胞治疗平台，我们的出版物表明， 该平台对原位高级别神经胶质瘤（KR 158 B，GL 261），第3组MB（NSC）， Sonic hedgehog MB（Ptc）和脑干胶质瘤（K2）。在本提案中，我们的目标是增加特异性 和通过采用针对胚胎肿瘤的更有针对性的方法的过继细胞治疗的功效， 特别是MB和脑干神经胶质瘤（BSG）。 最近的研究已经确定了个体发育和肿瘤学之间的联系，描述了 神经发育过程中的失调导致儿童中枢神经系统肿瘤，这表明这些癌症的发生 是异常发育过程的结果这为利用发展中国家的 神经组织作为抗MB和BSG的抗原来源。我们把这种基因组交叉点 发育组织和肿瘤作为发育抗原（DevAg）。在本提案中，我们将确定DevAgs 在MB和BSG两者中，并利用它们用于这些肿瘤的免疫靶向。靶向这些 发育调节的抗原不仅否定了原发性肿瘤切除的要求， 与正常基因产物的潜在交叉反应性。重要的是，这表明发育中的小脑 与MB的不同亚型共享免疫原性抗原，并且MB的多个亚型可以通过 发育抗原据我们所知，我们的研究是第一个。利用发育中的脑抗原 靶向同基因MB和BSG鼠模型和2.使用一种新的方法证明抗肿瘤功效， 靶向富集以选择特异性抗原。这种方法在安全和 有效地针对MB和BSG。

PROJECT SUMMARY/ABSTRACT: Brain tumors are the number one cause of cancer related deaths in children. Medulloblastoma (MB) is the most common malignant pediatric brain tumor, while brainstem gliomas (BSG) are the most lethal. Though numerous preclinical and clinical studies have demonstrated potential therapeutic benefits for immunotherapy in solid tumors, malignant brain tumors remain universally lethal. In response, our group has pioneered an adoptive cellular therapy platform that relies on the transfer of tumor-reactive T cells and our publications demonstrate that this platform is efficacious against orthotopic high grade gliomas (KR158B, GL261), Group 3 MB (NSC), Sonic hedgehog MB (Ptc), and brainstem glioma (K2). In this proposal, our objective is to increase the specificity and efficacy of adoptive cellular therapy by employing a more targeted approach against embryonal tumors, specifically MB and brainstem gliomas (BSG). Recent elegant studies have identified links between ontogeny and oncology, describing that dysregulation in neural developmental processes lead to childhood CNS tumors, suggesting these cancers arise as a consequence of abnormal developmental processes. This provides great opportunity to leverage developing neural tissue as a source of antigens against MB and BSG. We refer to this genomic intersection between developing tissue and tumors as developmental antigens (DevAg). In this proposal we will identify the DevAgs in both MB and BSG and leverage them for immunological targeting of these tumors. Targeting these developmentally regulated antigens not only negates the requirement for primary tumor resection but also limits potential cross-reactivity with normal gene products. Importantly, this indicates that developing cerebellum do share immunogenic antigens with different subtypes of MB and that multiple subtypes of MB can be targeted by developmental antigens. To our knowledge, our studies are the first to 1. Utilize developing brain antigens to target syngeneic MB and BSG murine models and 2. demonstrate antitumor efficacy using a novel method of targeted enrichment to select for specific antigens. This approach has profound implications in safely and effectively targeting MB and BSG.