Brain Tumor Targeting Using Tumor-Specific Neuroimmunology

描述(申请人提供)：恶性原发脑瘤是导致儿童和年轻人癌症死亡的最常见原因，其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脑瘤，中位生存期为15个月，低级别胶质瘤患者在10年内进展为普遍致命的肿瘤类型。目前的治疗方法是无能为力的，并受到对全身组织或周围能言善辩的大脑的非特异性毒性的限制；然而，免疫疗法承诺采用一种精确的方法。我们之前已经证明，可以针对肿瘤特异性突变EGFRvIII产生免疫反应。这些足以消除表达小鼠EGFRvIII同源物的原位胶质瘤，并预测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，而不会产生毒性。不幸的是，EGFRvIII是异质性表达的，肿瘤复发是由于EGFRvIII阴性的肿瘤细胞生长所致。最近，利用下一代测序，我们在胶质瘤中发现了另一个高度保守的肿瘤特异性突变，位于异柠檬酸脱氢酶1(IDH1)的活性部位。IDH1突变在几乎所有的胶质瘤亚型中都很常见(70%)，并且超过90%的IDH1突变是IDH1R132H。虽然IDH突变与更长的总生存期相关，但IDHR132H状态有时被误解为抑制肿瘤生长。相反，它表示IDH1R132H产生肿瘤代谢物R-2-羟基戊二酸(R-2HG)的一种遗传上不同的肿瘤亚群，它损害组蛋白和DNA去甲基酶，防止细胞分化，促进肿瘤发生。最近，IDH1R132H的小分子抑制作用被证明可以抑制肿瘤细胞的增殖，但它不能诱导细胞凋亡，肿瘤细胞持续对数生长。因此，作为一种治疗方法，小分子酶抑制可能只是部分有效的。我们实验室的初步数据显示，小鼠对IDH1R132H特异性多肽(PEPIDH1M)的免疫反应既具有免疫原性，又具有特异性。然而，与EGFRvIII不同的是，IDH突变在几乎所有的肿瘤细胞中都是均匀表达的。这项建议的具体目标将通过佐剂和宿主条件来优化PEPIDH1M疫苗接种，评估最佳疫苗策略的潜在毒性和有效性，并表征IDHR132H表达的胶质瘤患者血液样本中IDH1R132H的免疫呈现和识别。

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.