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：
9094714
负责人：
JOHN H. SAMPSON
金额：
$ 34.78万
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/9094714
关键词：
Accounting Active Sites Adjuvant Antigens Apoptosis Arginine Blood specimen Brain Brain Neoplasms Cell Proliferation Cell Respiration Cells Cessation of life 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 childhood cancer mortality clinically relevant conditioning conventional therapy experience genome-wide immunogenic immunogenicity inhibitor/antagonist logarithm melanoma mutant neoplastic cell neuroimmunology next generation sequencing peptide vaccination phase III trial prevent protein aminoacid sequence response safety testing small molecule small molecule inhibitor standard of care targeted treatment 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最常见的癌症死亡原因，并且死亡比肾脏或黑色素瘤的癌症更多。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，较低级别的神经胶质瘤患者在十年内发展为普遍致命的肿瘤类型。当前的治疗是无能的，并且受到对全身组织或周围雄辩大脑的非特异性毒性的限制。但是，免疫疗法有望采用精确的方法。我们以前已经证明，可以针对肿瘤特异性突变EGFRVIII专门产生免疫反应。这些足以消除表达EGFRVIII的鼠同源物的原位神经胶质瘤，并预测了在人类中产生免疫反应的能力。在患有脑肿瘤的人中，EGFRVIII特异性免疫反应足以始终消除所有表达无毒性的EGFRVIII肿瘤细胞。不幸的是，EGFRVIII是异质表达的，并且由于EGFRVIII阴性肿瘤细胞的生长而复发。最近，使用下一代测序，我们发现了在异氯酸酯脱氢酶1（IDH1）的活性位点的神经胶质瘤中的另一个高度保存和肿瘤特异性突变。在几乎所有神经胶质瘤亚型中，IDH1突变频繁（> 70％），超过90％的IDH1突变为IDH1R132H。尽管IDH突变与较长的总生存期有关，但IDHR132H状态偶尔被误解以作为肿瘤生长的抑制剂。相反，它表示IDH1R132H的遗传学上不同的子集，其中IDH1R132H产生了Onco-亚赛代谢物R-2-羟戊二酸酯（R-2HG），从而损害组蛋白和DNA脱甲基酶，可预防细胞分化并促进肿瘤发生。最近，已经证明对IDH1R132H的小分子抑制可减少肿瘤细胞的增殖。但是，它不会诱导凋亡，肿瘤细胞持续存在对数生长。因此，较小的分子酶抑制可能只能作为治疗方法部分有效。我们实验室的初步数据显示，使用IDH1R132H特异性肽（PEPIDH1M）对疫苗接种的鼠反应既具有免疫原性又是特异性的。然而，与Egfrviii不同，IDH突变在几乎所有肿瘤细胞中均匀表达。该提案的具体目的将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的潜力，并表征来自IDHR132H表达GlioMas患者的血液样本中IDH1R132H的免疫表现和识别。