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: 9767728
• 负责人: Kyle Dyson
• 金额: $ 5万
• 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/9767728
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Affect; 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 response; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Tissues; Toxic effect; Transcript; Variant; Xenograft Model; Xenograft procedure; anti-tumor immune response; antigen-specific T cells; 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; neoantigens; neoplastic cell; nerve stem cell; neurodevelopment; new therapeutic target; novel; novel therapeutics; preclinical efficacy; prevent; progenitor; prospective; protein expression; relating to nervous system; safety and feasibility; side effect; 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.

项目摘要/摘要 儿童脑瘤最近已超过白血病，成为与癌症相关的死亡的最常见原因 孩子们。利用细胞毒性T细胞的特异性进行的免疫治疗显示出前所未有的效果 对某些恶性肿瘤的治疗反应；然而，由于缺乏已知靶点，使其无法应用于 儿童脑肿瘤的治疗。摘要髓母细胞瘤是儿童最常见的恶性脑肿瘤。 据了解，现在至少包括四种不同的分子变体。第3组MB是最致命的，是 最常见的亚型。尽管使用了积极的治疗，但该组患者的总体存活率 3 MB保持在50%以下。严重的长期副作用和高复发率表明，更有针对性和 人们迫切需要有效的治疗方法。因此，这项提议的长期目标是开发一种 治疗高危MB的免疫学策略。在黑色素瘤中，最常见的免疫学 靶标是突变的蛋白质，产生肿瘤细胞特有的免疫原性表位(新抗原)。在……里面 与黑色素瘤相比，儿童脑肿瘤的突变发生率微不足道。表观遗传修饰因子 占主导地位的是少数反复突变的基因。在MB中，异常的表观遗传基因调控被证明是驱动 转录模式使人联想到多能干细胞和发育中的神经前体细胞。多能茎 因此，细胞和神经干细胞是发育调节抗原的潜在细胞来源。 (Dev AGS)，可用于启动免疫反应。这项提议的中心假设预示着 3MB组异常表达发育蛋白的免疫靶向将提供一种新的 这些患者的治疗平台具有增强的治疗潜力。这一假设将通过 三个具体目标：1)评价诱导多能干细胞的能力及其时空分布 不同的神经子代作为3MB组免疫靶向的抗原来源；2)确定 化疗、放疗和表观遗传修饰剂对Dev基因表达及抗肿瘤效应的影响 第3组MB肿瘤中的AGS；以及3)证实人类Dev抗原特异性T细胞靶向人类MB的能力 3MB组的体外和患者来源的异种移植模型中的肿瘤。目标1，将利用体外模型 神经发育以分析IPSCs和不同的IPSC来源的神经干细胞和 3 MB组的祖细胞(INSPC)，并将评估使用Dev靶向MB的特异性和有效性 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中的疗效 将对MB进行评估。这项研究具有重要意义，因为它将为获得抗原提供一种创新的策略 具有免疫靶向MB的能力，并证明这些抗原在引导 抗小鼠和人肿瘤的细胞毒性T细胞反应。