Developmentally regulated antigens for immunologic targeting of pediatric brain tumors

用于儿童脑肿瘤免疫靶向的发育调节抗原

基本信息

批准号：
10751884
负责人：
Catherine T Flores
金额：
$ 41.94万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751884
关键词：
Adoptive Cell Transfers Antigens Brain Brain Neoplasms Brain Stem Brain Stem Glioma Bypass Cancer Etiology Cerebellum Child Childhood Childhood Brain Neoplasm Childhood Central Nervous System Neoplasm Childhood Malignant Brain Tumor Clinical Research Data Dendritic Cells Development Developmental Process Disease Doctor of Philosophy Excision Genomics Glioma Growth Human Immune Targeting Immunologics Immunotherapy In Vitro Institution Lead Link Malignant Neoplasms Malignant neoplasm of brain Methods Molecular Oncology Outcome Physiologic pulse Pre-Clinical Model Primary Neoplasm Publications RNA Recurrence SHH gene Solid Neoplasm Source Specificity T-Lymphocyte Therapeutic Tissues Transcend brain tissue childhood cancer mortality cross reactivity efficacy evaluation gene product genomic profiles immunogenic in vivo medulloblastoma medulloblastoma cell line mouse model neoplastic cell neural novel phase 2 study postnatal preclinical study response safety and feasibility tumor

项目摘要

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.

项目摘要/摘要：脑肿瘤是儿童癌症相关死亡的第一大原因。髓母细胞瘤 (MB) 是最常见的恶性儿童脑肿瘤，而脑干胶质瘤（BSG）是最致命的。尽管大量临床前和临床研究已证明免疫疗法的潜在治疗益处实体瘤、恶性脑瘤仍然普遍致命。作为回应，我们的团队开创了一种收养依赖于肿瘤反应性 T 细胞转移的细胞治疗平台，我们的出版物证明了该平台对原位高级神经胶质瘤（KR158B、GL261）、第 3 组 MB (NSC) 有效， Sonic Hedgehog MB (Ptc) 和脑干胶质瘤 (K2)。在这个提案中，我们的目标是提高特异性以及采用更有针对性的方法对抗胚胎肿瘤的过继细胞疗法的功效，特别是MB和脑干胶质瘤（BSG）。最近的优雅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的失调导致儿童中枢神经系统肿瘤，表明这些癌症的发生异常发育过程的结果。这为利用发展提供了绝佳的机会神经组织作为针对 MB 和 BSG 的抗原来源。我们将这种基因组交叉称为发育中的组织和肿瘤作为发育抗原（DevAg）。在此提案中，我们将确定 DevAgs 并利用它们对这些肿瘤进行免疫靶向。针对这些发育调节抗原不仅否定了原发肿瘤切除的要求，而且限制了与正常基因产物的潜在交叉反应。重要的是，这表明发育中的小脑确实与MB的不同亚型共享免疫原性抗原，并且MB的多种亚型可以通过发育抗原。据我们所知，我们的研究是第一个： 1. 利用正在发育的脑抗原来 2. 使用一种新方法证明抗肿瘤功效靶向富集以选择特定抗原。这种方法对于安全和有效针对MB和BSG。