Brain Tumor Targeting Using Tumor-Specific Neuroimmunology

使用肿瘤特异性神经免疫学靶向脑肿瘤

基本信息

批准号：
8922079
负责人：
JOHN H. SAMPSON
金额：
$ 34.74万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8922079
关键词：
Accounting Active Sites Adjuvant Antigens Apoptosis Arginine Blood specimen Brain Brain Neoplasms Cancer Etiology Cell Proliferation Cell Respiration Cells Cessation of life Child Clinical Codon Nucleotides CpG Island Methylator Phenotype DNA Data Dependence Enzyme Inhibition Enzymes Epidermal Growth Factor Receptor Epigenetic Process Frequencies Glioblastoma Glioma Growth Health Histidine Histones Homologous Gene Human Immune Immune response Immunocompetent Immunotherapy International Isocitrate Dehydrogenase Isocitrates Laboratories Lymphopenia Malignant - descriptor Malignant Glioma Maps Methylation Mus Mutation Oncogenic Patients Peptide Vaccines Peptides Primary Brain Neoplasms Renal carcinoma Research Specificity T-Lymphocyte Testing Therapeutic Therapeutic Intervention Tissues Toxic effect Tumor Antigens Tumorigenicity Vaccination Vaccines Variant base cell killing chemotherapy clinically relevant conditioning conventional therapy experience genome-wide immunogenic immunogenicity inhibitor/antagonist isocitrate melanoma mutant neoplastic cell neuroimmunology next generation sequencing phase III trial prevent protein aminoacid sequence response safety testing small molecule standard of care temozolomide tumor tumor growth tumorigenesis young adult

项目摘要

DESCRIPTION (provided by applicant): Malignant primary brain tumors are the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Glioblastoma, the most malignant primary brain tumor, has a median survival of <15 months, and patients with lower grade gliomas progress to the universally lethal tumor types within ten years. Current therapy is incapacitating and limited by non-specific toxicity to systemic tissue or surrounding eloquent brain; however, immunotherapy promises an exquisitely precise approach. We have previously demonstrated that immune responses can be generated specifically against the tumor-specific mutation, EGFRvIII. These were sufficient to eliminate orthotopic gliomas expressing a murine homologue of EGFRvIII and predicted the ability to generate immune responses in humans. In humans with brain tumors, EGFRvIII-specific immune responses were sufficient to consistently eliminate all EGFRvIII-expressing tumors cells without toxicity. Unfortunately, EGFRvIII is heterogeneously expressed and tumors recur as a result of outgrowth of the EGFRvIII negative tumor cells. Recently, using next-generation sequencing, we discovered another highly-conserved and tumor-specific mutation in gliomas at the active site of isocitrate dehydrogenase 1 (IDH1). IDH1 mutations are frequent (>70%) in almost all glioma subtypes, and greater than 90% of IDH1 mutations are IDH1R132H. Although IDH mutations are associated with longer overall survival, IDHR132H status has been occasionally misunderstood to function as an inhibitor of tumor growth. Rather, it denotes a genetically distinct subset of tumors where IDH1R132H generates the onco-metabolite R-2- hydroxyglutarate (R-2HG) which impairs histone and DNA demethylases, prevents cellular differentiation, and promotes tumorigenesis. Recently, small molecule inhibition of IDH1R132H has been shown to reduce tumor cell proliferation; however, it does not induce apoptosis and tumor cells persist in logarithmic growth. Thus small molecule enzyme inhibition may only be partially effective as a therapeutic approach. Preliminary data from our laboratory shows murine responses to vaccination with an IDH1R132H-specific peptide (PEPIDH1M) are both immunogenic and specific. Unlike EGFRvIII, however, the IDH mutation is homogeneously expressed in nearly all tumor cells. The specific aims of this proposal will optimize PEPIDH1M vaccination through adjuvants and host conditioning, assess potential for toxicity and efficacy of the optimal vaccine strategy, and characterize immune presentation and recognition of IDH1R132H in blood samples from patients with IDHR132H-expressing gliomas.

描述（由申请人提供）：恶性原发性脑肿瘤是儿童和年轻人癌症死亡的最常见原因，比肾癌或黑色素瘤造成的死亡人数更多。胶质母细胞瘤是最恶性的原发性脑肿瘤，中位生存期<15个月，低级别胶质瘤患者在十年内进展为普遍致命的肿瘤类型。目前的治疗由于对全身组织或周围大脑的非特异性毒性而导致丧失能力并受到限制；然而，免疫疗法有望提供一种极其精确的方法。我们之前已经证明，可以针对肿瘤特异性突变 EGFRvIII 产生特异性免疫反应。这些足以消除表达 EGFRvIII 鼠同源物的原位神经胶质瘤，并预测其在人类中产生免疫反应的能力。在患有脑肿瘤的人类中，EGFRvIII 特异性免疫反应足以持续消除所有表达 EGFRvIII 的肿瘤细胞，且无毒性。不幸的是，EGFRvIII 表达异质，并且由于 EGFRvIII 阴性肿瘤细胞的生长，肿瘤复发。最近，利用新一代测序，我们在神经胶质瘤中的异柠檬酸脱氢酶 1 (IDH1) 活性位点发现了另一个高度保守的肿瘤特异性突变。 IDH1突变在几乎所有神经胶质瘤亚型中都很常见（>70%），并且超过90%的IDH1突变是IDH1R132H。尽管 IDH 突变与较长的总生存期相关，但 IDHR132H 状态偶尔会被误解为肿瘤生长的抑制剂。相反，它指的是一个遗传上不同的肿瘤子集，其中 IDH1R132H 产生肿瘤代谢物 R-2-羟基戊二酸 (R-2HG)，该代谢物会损害组蛋白和 DNA 去甲基化酶、阻止细胞分化并促进肿瘤发生。最近，IDH1R132H 的小分子抑制已被证明可以减少肿瘤细胞增殖；然而，它不会诱导细胞凋亡，肿瘤细胞持续呈对数生长。因此，小分子酶抑制作为治疗方法可能仅部分有效。我们实验室的初步数据显示，小鼠对 IDH1R132H 特异性肽 (PEPIDH1M) 疫苗接种的反应既具有免疫原性又具有特异性。然而，与 EGFRvIII 不同的是，IDH 突变在几乎所有肿瘤细胞中均匀表达。该提案的具体目标是通过佐剂和宿主调节来优化 PEPIDH1M 疫苗接种，评估最佳疫苗策略的毒性和功效潜力，并表征 IDHR132H 表达神经胶质瘤患者血液样本中 IDH1R132H 的免疫呈递和识别。