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The value of EGFRvIII as the target for glioma vaccines.

ABSTRACT: Malignant brain tumors continue to be rapidly progressive and resistant to most treatments. Even with state-of-the-art standard of care (surgery, chemotherapy, and radiotherapy) long-term survival in the last 80 years improved from 6 to 15 months. Improved imaging has also likely contributed to prolonged survival. Immunotherapy for cancer dates back to publications from 1742. The central idea is that the immune system can detect and eliminate foreign antigens, either from infectious agents or tumors, and thus could be therapeutic in brain tumors. Recent introduction of immune modulators of cytotoxic T-lymphocyte antigen (CTLA)-4 and programmed cell death 1/programmed cell death 1 ligand (PD-1/PDL1) add much excitement to this field. For brain tumors, there are several ongoing phase I and III trials to determine whether any of the current immunotherapy approaches can demonstrate activity in randomized, controlled double-blinded trials-with ongoing and historical trials presented in tables within the manuscript. Immunotherapy has explored the use of various types of antigens (obtained either from homogenates of patients' tumors or synthetically produced), and various immunization procedures and adjuvants. Glioma antigens have also been isolated from the patients' own tumor, then produced in vitro (for example the glioma antigen EGFRvIII), and used to immunize patients directly, or with carriers such as dendritic cells with or without additional adjuvants. Several of these practical approaches are currently in phase III trials. Remaining challenges are how to increase the percentage of complete responses and response duration, and the enigmatic absence of an almost total lack of adverse brain inflammation following immunization of brain tumor patients, as has been observed following immunization against brain antigens in other diseases, such as Alzheimer's Disease.

SUBMITTER: Lowenstein PR

PROVIDER: S-EPMC4438702 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The value of EGFRvIII as the target for glioma vaccines.

Lowenstein Pedro R PR Castro Maria G MG

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 20140101

Malignant brain tumors continue to be rapidly progressive and resistant to most treatments. Even with state-of-the-art standard of care (surgery, chemotherapy, and radiotherapy) long-term survival in the last 80 years improved from 6 to 15 months. Improved imaging has also likely contributed to prolonged survival. Immunotherapy for cancer dates back to publications from 1742. The central idea is that the immune system can detect and eliminate foreign antigens, either from infectious agents or tu ...[more]

PMID: 24857059

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Project description:Molecular pathology and personalized medicine are still being evolved in Saudi Arabia, and genetic testing for the detection of mutations as cancer markers have not been established in the diagnostics laboratories in Saudi Arabia. The aim of the present study was to determine the prevalence of isocitrate dehydrogenase (IDH1 and IDH2) mutations and epidermal growth factor receptor variant (EGFRv)III transcript expression in Saudi Arabian patients with glioma. Out of 117 brain tumors tested by reverse transcription-quantitative PCR for EGFRvIII, 41 cases tested positive. In the glioblastoma (GBM) category, 28/55 tumors were positive, in astrocytoma tumors 5/22, and in oligodendrogliomas 4/13 cases were positive respectively. EGFRvIII transcript was sequenced by capillary electrophoresis to demonstrate the presence of EGFRvIII-specific junction where exons 2-7 were deleted. In the present study 106 tumors were sequenced for IDH1 exon-4 mutations using the capillary sequencing method. The most common substitution missense mutation c.395G>A was found in 16 tumors. In the case of adamantinomatous craniopharyngioma, a novel missense mutation in c.472C>T was detected in IDH2 gene. Using next-generation sequencing (NGS), 74 tumors were sequenced for the IDH1 gene, and a total of 8 missense variants were identified in 36 tumors in a population of Saudi Arabia. The missense mutation (c.395G>A) was detected in 29/36 of tumors. A novel intronic mutation in c.414+9T>A was found in 13 cases in the IDH1 gene. In addition, one case exhibited a novel synonymous mutation in c.369A>G. Eleven tumors were found to have compound mutations in the IDH1 gene. In IDH2 gene, out of a total of 16 variants found in 6 out of 45 tumors, nine were missense, five were synonymous and one was intronic. This is the first report from Saudi Arabian laboratories analyzing glioma tumors for EGFRvIII expression, and the first study from Saudi Arabia to analyze IDH mutations in gliomas using the capillary and NGS methods.

Project description:Conventional therapies for malignant gliomas (MGs) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by non-specific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in MGs and other neoplasms. This mutation encodes a constitutively active tyrosine kinase that enhances tumorgenicity and migration and confers radiation and chemotherapeutic resistance. This in-frame deletion mutation splits a codon resulting in the creation of a novel glycine at the fusion junction between normally distant parts of the molecule and producing a sequence re-arrangement which creates a tumor-specific epitope for cellular or humoral immunotherapy in patients with MGs. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction is an efficacious immunotherapy in syngeneic murine models, but patients with MGs have a profound immunosuppression that may inhibit the ability of antigen presenting cells (APCs), even those generated ex vivo, to induce EGFRvIII-specific immune responses. In this report, we summarize our results in humans targeting this mutation in two consecutive and one multi-institutional Phase II immunotherapy trials. These trials demonstrated that vaccines targeting EGFRvIII are capable of inducing potent T- and B-cell immunity in these patients, and lead to an unexpectedly long survival time. Most importantly, vaccines targeting EGFRvIII were universally successful at eliminating tumor cells expressing the targeted antigen without any evidence of symptomatic collateral toxicity. These studies establish the tumor-specific EGFRvIII mutation as a novel target for humoral- and cell-mediated immunotherapy in a variety of cancers. The recurrence of EGFRvIII-negative tumors in our patients, however, highlights the need for targeting a broader repertoire of tumor-specific antigens.

Project description:m6A RNA methylation regulators can regulate the growth, progression, and invasion of glioma cells by regulating their target genes, which provides a reliable support for the m6A regulator-target axes as the novel therapeutic targets and clinical prognostic signature in glioma. This study aimed to explore the role and prognostic value of m6A RNA methylation regulators and their targets. Expression profiles and clinicopathological data were obtained from the Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Clinical Proteome Tumor Analysis Consortium (CPTAC) datasets. Differential expression and correlation analyses were performed between normal and glioma tissues at mRNA and protein levels. Univariate Cox regression, survival, and Lasso Cox regression analyses were conducted to identify and establish the prognostic gene signature. Kaplan-Meier curve, multivariate Cox regression analysis, and ROC were utilized to evaluate the prognostic capacity of the prognostic gene signature. The correlation analysis, systematic bioinformatics analysis, and cell experiment were performed to further understand the potential underlying molecular mechanisms and drug sensitivity. Our results suggested that IGF2BP2, KIAA1429, METTL16, and METTL3, as well as 208 targets are involved in the occurrence of glioma, GBM, and LGG. YTHDF1 and 78 targets involved the occurrence of glioma and GBM, not LGG, among which 181 genes were associated with overall survival. From other findings and our cell experiment results, we demonstrated that METTL3 can activate Notch pathway and facilitate glioma occurrence through regulating its direct targets NOTCH3, DLL3, and HES1, and Notch pathway genes may serve as the potential treatment targets for glioma. Our study established and validated a seven-gene signature comprising METTL3, COL18A1, NASP, PHLPP2, TIMP1, U2AF2, and VEGFA, with a good capability for predicting glioma survival, which may guide therapeutic customization and clinical decision-making. These genes were identified to influence 81 anticancer drug responses, which further contributes to the early phase clinical trials of drug development.

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The value of EGFRvIII as the target for glioma vaccines.

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The value of EGFRvIII as the target for glioma vaccines.

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