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，低级别胶质瘤患者在10年内发展为普遍致命的肿瘤类型。目前的治疗是失能性的，并且受限于对全身组织或周围大脑的非特异性毒性；然而，免疫疗法承诺了一种非常精确的方法。我们之前已经证明，免疫反应可以针对肿瘤特异性突变EGFRvIII产生特异性。这些足以消除表达EGFRvIII小鼠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。在脑肿瘤患者中，egfrviii特异性免疫反应足以持续消除所有表达egfrviii的肿瘤细胞而没有毒性。不幸的是，EGFRvIII是异质表达的，肿瘤复发是EGFRvIII阴性肿瘤细胞生长的结果。最近，利用下一代测序，我们在胶质瘤的异柠檬酸脱氢酶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突变在几乎所有胶质瘤亚型中都很常见（约70%），其中IDH1突变为IDH1R132H的占比超过90%。虽然IDH突变与更长的总生存期相关，但IDHR132H状态偶尔被误解为肿瘤生长抑制剂。相反，它表示一个遗传上不同的肿瘤亚群，其中IDH1R132H产生肿瘤代谢物R-2-羟戊二酸（R-2HG），其损害组蛋白和DNA去甲基化酶，阻止细胞分化并促进肿瘤发生。最近，小分子抑制IDH1R132H已被证明可以减少肿瘤细胞的增殖；然而，它不会诱导细胞凋亡，肿瘤细胞持续呈对数生长。因此，作为一种治疗方法，小分子酶抑制可能只是部分有效。我们实验室的初步数据显示，小鼠对接种idh1r132h特异性肽（PEPIDH1M）的反应既具有免疫原性，也具有特异性。然而，与EGFRvIII不同的是，IDH突变在几乎所有肿瘤细胞中均表达。该提案的具体目的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潜在毒性和有效性，并表征表达idhr132h的胶质瘤患者血液样本中IDH1R132H的免疫表现和识别。

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.