Immunologic Targeting of Developmentally-Regulated Antigens for the Treatment of High-Risk Medulloblastoma

发育调节抗原的免疫靶向治疗高风险髓母细胞瘤

• 批准号: 9397160
• 负责人: Kyle Dyson
• 金额: $ 3.81万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9397160
• 关键词: Adoptive Transfer; Adverse effects; Affect; Alpha Cell; Animals; Antigens; Autoimmune Process; Autologous; Brain; Brain Neoplasms; Cancer Etiology; Categories; Cells; Cerebellum; Cessation of life; Child; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Clinical Trials; Clonal Evolution; Cognitive deficits; Collection; Coupled; Cytotoxic T-Lymphocytes; Development; Disease; Doctor of Philosophy; Effectiveness; Epigenetic Process; Epitopes; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Goals; High Prevalence; Histologic; Histone Deacetylase Inhibitor; Human; Immune; Immune Targeting; Immune response; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Maintenance; Malignant Neoplasms; Methods; Molecular; Morbidity - disease rate; Mus; Mutate; Mutation; Operative Surgical Procedures; Patients; Pattern; Pluripotent Stem Cells; Population; Prevalence; Proteins; RNA; Radiation; Recurrence; Refractory; Relapse; Reporting; Research; Risk; SHH gene; Second Primary Cancers; Source; Specificity; Stem cells; Subgroup; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Tissues; Toxic effect; Transcript; Variant; Viral Tumor Antigens; Xenograft Model; Xenograft procedure; base; cancer therapy; chemotherapy; childhood cancer mortality; cross reactivity; design; effective therapy; falls; high risk; histone methylation; immune activation; immune function; immunogenic; immunogenicity; in vitro Model; induced pluripotent stem cell; innovation; leukemia; medulloblastoma; melanoma; molecular subtypes; mouse model; neoplastic cell; nerve stem cell; neurodevelopment; new therapeutic target; novel; novel therapeutics; preclinical efficacy; prevent; progenitor; prospective; protein expression; relating to nervous system; response; safety and feasibility; spatiotemporal; standard care; stem; stem-like cell; targeted treatment; transcriptome; treatment response; tumor

PROJECT SUMMARY/ABSTRACT Pediatric brain tumors have recently surpassed leukemia as the most common cause of cancer-related death in children. Immunotherapies leveraging the specificity of cytotoxic T cells have demonstrated unprecedented treatment responses for some malignancies; however, a lack of known targets prevents its application to the treatment of pediatric brain tumors. Medulloblastoma (MB) is the most common malignant pediatric brain tumor and is now understood to include at least four distinct molecular variants. Group 3 MB is the deadliest and among the most prevalent subtypes. Despite the use of aggressive treatments, the overall survival of patients with Group 3 MB remains below 50%. Serious long-term side effects and high relapse rates indicate that more targeted and effective therapies are desperately needed. Thus, the long-term goal of this proposal is to develop an immunologic strategy for treating high-risk MB. In melanoma, the most commonly appreciated immunologic targets are mutated proteins that generate immunogenic epitopes unique to tumor cells (neoantigens). In contrast to melanoma, the prevalence of mutations in pediatric brain tumors is paltry. Epigenetic modifiers predominate the few recurrently mutated genes. In MB, aberrant epigenetic gene regulation is shown to drive transcription patterns reminiscent of pluripotent stem cells and developing neural precursors. Pluripotent stem cells and neural stem cells therefore represent potential cellular sources of developmentally-regulated antigens (Dev Ags) that can be used to prime immune responses. The central hypothesis of this proposal portends that immunologic targeting of aberrantly expressed developmental proteins in Group 3 MB will provide a novel therapeutic platform with enhanced curative potential for these patients. This hypothesis will be tested through three specific aims: 1) Evaluate the capacity of induced pluripotent stem cells (iPSCs) and their spatiotemporally distinct neural progeny to serve as sources of antigen for immunologic targeting of Group 3 MB; 2) Determine the effect of chemotherapy, radiation, and epigenetic modifiers on the expression and anti-tumor efficacy of Dev Ags in Group 3 MB tumors; and 3) Demonstrate the ability of human Dev Ag specific T cells to target human MB tumors in vitro and in a patient-derived xenograft model of Group 3 MB. Aim 1, will utilize an in vitro model of neurodevelopment to analyze the transcriptional overlap of iPSCs and distinct iPSC-derived neural stem and progenitors (iNSPCs) with Group 3 MB and will evaluate the specificity and efficacy for targeting MB using Dev Ag T cells. Aim 2 will evaluate changes in gene expression, T cell specificity, and anti-tumor efficacy following exposure of MB tumors to radiation, chemotherapy, and epigenetic modifiers. Finally, using autologous iPSCs, iNSPCs, immune cells, and MB tumors, the efficacy of Dev Ag T cells in patient-derived xenografts of Group 3 MB will be evaluated. This research is significant in that it will provide an innovative strategy for deriving antigens with the capacity to immunologically target MB and demonstrate the effectiveness of these antigens at directing cytotoxic T cell responses against mouse and human tumors.

项目总结/摘要 儿童脑肿瘤最近已超过白血病，成为2010年癌症相关死亡的最常见原因。 孩子利用细胞毒性T细胞的特异性的免疫疗法已经证明是前所未有的 一些恶性肿瘤的治疗反应;然而，缺乏已知的靶点阻止了其应用于 小儿脑肿瘤的治疗髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤 并且现在被理解为包括至少四种不同的分子变体。第3组MB是最致命的， 最常见的亚型尽管使用了积极的治疗，但该组患者的总生存率 3 MB仍然低于50%。严重的长期副作用和高复发率表明，更有针对性和 迫切需要有效的治疗方法。因此，本提案的长期目标是制定一项 治疗高危MB免疫策略。在黑色素瘤中，最常见的免疫学 靶是产生肿瘤细胞特有的免疫原性表位（新抗原）的突变蛋白质。在 与黑色素瘤相比，儿童脑肿瘤中突变的发生率微不足道。表观遗传修饰剂 占主导地位的几个反复突变的基因。在MB中，异常的表观遗传基因调控被证明是驱动 转录模式让人联想到多能干细胞和发育中的神经前体。多能干 因此，细胞和神经干细胞代表了发育调节抗原的潜在细胞来源 (Dev抗原），可用于引发免疫反应。这一建议的核心假设预示着， 在第3组MB中异常表达的发育蛋白的免疫靶向将提供一种新的 为这些患者提供具有增强的治疗潜力的治疗平台。这一假设将通过 三个具体目标：1）评估诱导多能干细胞（iPSC）的能力及其时空 不同的神经子代充当用于组3 MB的免疫靶向的抗原来源; 2）确定 化疗、放疗和表观遗传修饰对Dev表达和抗肿瘤疗效的影响 3）证明人Dev Ag特异性T细胞靶向人MB的能力 在体外和第3 MB组的患者来源的异种移植物模型中的肿瘤。目的1，将利用体外模型， 用于分析iPSC和不同iPSC衍生的神经干细胞的转录重叠， 使用第3组MB检测iNSPCs，并将使用Dev Ag T细胞。目的2将评估基因表达，T细胞特异性和抗肿瘤疗效的变化， MB肿瘤暴露于放射、化疗和表观遗传修饰剂。最后，使用自体iPSC， iNSPC、免疫细胞和MB肿瘤，Dev Ag T细胞在第3组患者来源的异种移植物中的功效 将对MB进行评估。这项研究意义重大，因为它将为衍生抗原提供创新策略 具有免疫靶向MB的能力，并证明了这些抗原在指导 针对小鼠和人肿瘤的细胞毒性T细胞应答。