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.
Gliomas are the most common malignant primary brain tumor and remain uniformly lethal. Conventional therapy for malignant gliomas is incapacitating and limited by non-specific toxicity to systemic tissue or surrounding eloquent brain. This research will test the safety and potential efficacy of a tumor-specific vaccine targeted against the homogeneously expressed and tumor-specific mutation, IDH1R132H.
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