权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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/文摘