Peptide Vaccination Targeting Tumor-Specific IDH1R132H Mutation for Brain Tumors

恶性原发脑瘤是导致儿童和青年癌症死亡的最常见原因 与肾癌或黑色素瘤相比，成年人的死亡人数更多。恶性程度最高的胶质母细胞瘤 原发脑瘤，中位生存期为15个月，低级别胶质瘤患者通常 在10年内向普遍致命的肿瘤类型发展。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；然而，免疫疗法承诺 非常精确的方法。我们之前已经证明，免疫反应可以产生 针对肿瘤特异性突变EGFRvIII。这些足以消除原位胶质瘤。 表达了EGFRvIII的小鼠同源物，并预测了在 人类。在脑瘤患者中，EGFRvIII特异性免疫反应足以始终如一地 消除所有表达EGFRvIII的肿瘤细胞，而不会产生毒性。不幸的是，EGFRvIII是异质的 表达和肿瘤复发是由于EGFRvIII阴性的肿瘤细胞的生长。 最近，利用下一代测序，我们发现了另一个高度保守的肿瘤-- 脑胶质瘤中异柠檬酸脱氢酶1活性部位的特异性突变。IDH1突变是 IDH1R132H在几乎所有胶质瘤亚型中都很常见(&gt；70%)，并且超过90%的IDH1突变是IDH1R132H。 尽管IDH突变与更长的总生存期相关，IDH1R132H状态偶尔会出现 被误解为具有抑制肿瘤生长的作用。相反，它指的是基因上不同的子集 IDH1R132H产生损害组蛋白的肿瘤代谢物R-2-羟基戊二酸(R-2HG)的肿瘤 和DNA去甲基酶，防止细胞分化，促进肿瘤发生。最近，小米 IDH1R132H的分子抑制已被证明能抑制肿瘤细胞的增殖；然而，它不能诱导 细胞凋亡和肿瘤细胞持续对数生长。因此，小分子酶抑制可能只是 作为一种治疗方法，部分有效。 我们实验室的初步数据显示，小鼠对IDH1R132H特异性疫苗的反应 多肽(PEPIDH1M)具有免疫原性和特异性。此外，试点数据表明PEPIDH1M诱导 免疫应答在体内外识别和溶解IDH1R132H阳性肿瘤。然而，与EGFRvIII不同的是， IDH突变在几乎所有的肿瘤细胞中均有表达。这项提案的具体目标将是 (1)优化PEPIDH1M的免疫原性和抗肿瘤效果(2)评价其安全性和潜在毒性 IDH1R132H用于IND应用的靶向疫苗的研究和(3)进行优化的IDH1R132H的临床试验 进行多肽疫苗接种以评估安全性和免疫原性。

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 usually progress to the universally lethal tumor types within 10 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 tumor 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, IDH1R132H 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. Moreover, pilot data indicates PEPIDH1M-induced immune responses recognize and lyse IDH1R132H positive tumor in vitro and in vivo. Unlike EGFRvIII, however, the IDH mutation is homogeneously expressed in nearly all tumor cells. The specific aims of this proposal will (1) optimize the immunogenicity and anti-tumor efficacy of PEPIDH1M (2) assess the safety and potential toxicity of IDH1R132H targeted vaccination for IND application and (3) conduct a clinical trial of an optimized IDH1R132H peptide vaccination to assess safety and immunogenicity.