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: 10246430
• 负责人: Kyle Dyson
• 金额: $ 2.83万
• 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 2022-08-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246430
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Affect; Animals; Antigens; Autologous; Brain; Brain Neoplasms; Cancer Etiology; Categories; Cells; Cerebellum; Cessation of life; Chemotherapy and/or radiation; 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; Gene set enrichment analysis; 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; Relapse; Reporting; Research; Risk; SHH gene; Second Primary Cancers; Source; Specificity; Subgroup; T cell response; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Tissues; Toxic effect; Transcript; Variant; aggressive therapy; anti-tumor immune response; antigen-specific T cells; autoimmune toxicity; base; cancer therapy; chemotherapy; childhood cancer mortality; cross reactivity; design; effective therapy; effectiveness evaluation; efficacy evaluation; 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; patient derived xenograft model; preclinical efficacy; prevent; progenitor; prospective; protein expression; refractory cancer; relating to nervous system; safety and feasibility; side effect; spatiotemporal; standard care; stem; stem cells; 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.

项目概要/摘要 最近，小儿脑肿瘤已超过白血病，成为儿童癌症相关死亡的最常见原因。 孩子们。利用细胞毒性 T 细胞特异性的免疫疗法已被证明是前所未有的 某些恶性肿瘤的治疗反应；然而，缺乏已知的目标阻碍了其应用于 治疗小儿脑肿瘤。髓母细胞瘤（MB）是最常见的恶性小儿脑肿瘤 现在被认为包括至少四种不同的分子变体。 3 MB 组是最致命的，也是其中最致命的 最常见的亚型。尽管采用了积极的治疗，该组患者的总生存率 3 MB 仍低于 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开发一个 治疗高危MB的免疫策略。在黑色素瘤中，最常见的免疫学 靶标是突变蛋白，可产生肿瘤细胞特有的免疫原性表位（新抗原）。在 与黑色素瘤相比，儿童脑肿瘤的突变发生率微乎其微。表观遗传修饰因子 主导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可以驱动 转录模式让人想起多能干细胞和发育中的神经前体细胞。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 Ags）可用于引发免疫反应。该提案的中心假设预示着 针对第 3 组 MB 中异常表达的发育蛋白的免疫学靶向将提供一种新的方法 为这些患者提供增强治疗潜力的治疗平台。该假设将通过以下方式进行检验 三个具体目标：1）评估诱导多能干细胞（iPSC）的能力及其时空能力 不同的神经后代作为第 3 组 MB 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 表达和抗肿瘤功效的影响 3组MB肿瘤中的Ag； 3) 展示人类 Dev Ag 特异性 T 细胞靶向人类 MB 的能力 体外肿瘤和 3 MB 组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 神经发育分析 iPSC 和不同 iPSC 衍生神经干的转录重叠 具有第 3 组 MB 的祖细胞 (iNSPC)，并将使用 Dev 评估靶向 MB 的特异性和功效 银 T 细胞。目标 2 将评估基因表达、T 细胞特异性和抗肿瘤功效的变化 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 MB 将被评估。这项研究的意义重大，因为它将提供一种创新的抗原衍生策略 具有免疫靶向 MB 的能力，并证明这些抗原在指导方面的有效性 针对小鼠和人类肿瘤的细胞毒性 T 细胞反应。