Brain Tumor Targeting Using Tumor-Specific Neuroimmunology

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，死亡人数超过肾癌或黑色素瘤。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，并且具有较低级别胶质瘤的患者在十年内进展为普遍致命的肿瘤类型。目前的治疗是失能的，并受到全身组织或周围功能脑的非特异性毒性的限制;然而，免疫治疗有望成为一种非常精确的方法。我们以前已经证明，免疫反应可以产生特异性针对肿瘤特异性突变，EGFRvIII。这些足以消除表达EGFRvIII的鼠同源物的原位神经胶质瘤，并预测在人类中产生免疫应答的能力。在患有脑肿瘤的人类中，EGFRvIII特异性免疫应答足以持续消除所有表达EGFRvIII的肿瘤细胞而无毒性。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导致肿瘤复发。最近，利用新一代测序技术，我们在异柠檬酸脱氢酶1（IDH 1）的活性位点发现了另一个高度保守的肿瘤特异性突变。IDH 1突变在几乎所有胶质瘤亚型中都很常见（>70%），超过90%的IDH 1突变是IDH 1 R132 H。虽然IDH突变与较长的总生存期相关，但IDHR 132 H状态偶尔被误解为肿瘤生长的抑制剂。相反，它表示遗传上不同的肿瘤子集，其中IDH 1 R132 H产生致癌代谢物R-2-羟基戊二酸（R-2 HG），其损害组蛋白和DNA脱甲基酶，阻止细胞分化，并促进肿瘤发生。最近，IDH 1 R132 H的小分子抑制已经显示出减少肿瘤细胞增殖;然而，它不诱导凋亡，并且肿瘤细胞持续对数生长。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，对IDH 1 R132 H特异性肽（PEPIDH 1 M）接种的鼠应答具有免疫原性和特异性。然而，与EGFRvIII不同，IDH突变在几乎所有肿瘤细胞中均质表达。该提案的具体目标是通过佐剂和宿主调节优化PEPIDH 1 M疫苗接种，评估最佳疫苗策略的潜在毒性和有效性，并表征IDHR 132 H表达胶质瘤患者血液样本中IDH 1 R132 H的免疫呈递和识别。

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.