Background: Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the 'cold' tumor phenotype. Inhibiting D-2HG production presents an opportunity to generate a robust antitumor response following tumor antigen vaccination and immune checkpoint blockade.
Methods: An IDH1 glioma model was created in syngeneic -transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1 mutation-derived neoepitope. The effects of an orally available inhibitor of mutant IDH1 and IDH2, AG-881, were evaluated as monotherapy and in combination with the IDH1 peptide vaccination or anti-PD-1 immune checkpoint blockade.
Results: The -syngeneic IDH1 cell line expressed the IDH1 mutant protein and formed D-2HG producing orthotopic gliomas in vivo. Treatment of tumor-bearing mice with AG-881 resulted in a reduction of D-2HG levels in IDH1 glioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1 gliomas. AG-881 monotherapy suppressed the progression of IDH1 gliomas in a CD4 and CD8 cell-dependent manner, enhanced proinflammatory IFNγ-related gene expression, and increased the number of CD4 tumor-infiltrating T-cells. Prophylactic vaccination with the HLA-DR1-restricted IDH1 peptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1 and DR1-IDH1 peptides in combination with the IDH inhibitor significantly prolonged survival. Finally, tumor-bearing mice treated with both AG-881 and a PD-1 blocking antibody demonstrated improved survival when compared with either treatment alone.
Conclusion: The development of effective IDH1-targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our -syngeneic IDH1 glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.
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http://dx.doi.org/10.1136/jitc-2022-004644 | DOI Listing |
Transl Cancer Res
December 2024
Department of Radiation Oncology, The Second Hospital of Lanzhou University, Lanzhou, China.
Background: Within the realm of primary brain tumors, specifically glioblastoma (GBM), presents a notable obstacle due to their unfavorable prognosis and differing median survival rates contingent upon tumor grade and subtype. Despite a plethora of research connecting cardiotrophin-1 (CTF1) modifications to a range of illnesses, its correlation with glioma remains uncertain. This study investigated the clinical value of CTF1 in glioma and its potential as a biomarker of the disease.
View Article and Find Full Text PDFActa Neuropathol Commun
January 2025
Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
Glioblastoma is the deadliest primary brain tumor, largely due to inevitable recurrence of the disease after treatment. While most recurrences are local, patients rarely present with a new discontiguous focus of glioblastoma. Little is currently known about the genetic profile of discontiguous recurrences.
View Article and Find Full Text PDFJ Mol Neurosci
January 2025
Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
Hemorrhagic stroke is a known complication of glioma, yet the underlying mechanisms remain poorly understood. This study aims to investigate key biomarkers of glioma-related hemorrhage to provide insights into glioma molecular therapies. Data were obtained from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases to analyze differentially expressed genes (DEGs) in glioma by contrasting glioblastoma (GBM) with low-grade gliomas (LGGs).
View Article and Find Full Text PDFTher Clin Risk Manag
January 2025
Department of Oncology, Gaoxin Branch of the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, People's Republic of China.
Background: The relationship between molecular phenotype and prognosis in high-grade gliomas (WHO III and IV, HGG) treated with radiotherapy and chemotherapy is not fully understood and needs further exploration.
Methods: The HGG patients following surgery and treatment with radiotherapy and chemotherapy. Univariate and multivariate Cox analyses were used to assess the independent prognostic factors.
Proc Natl Acad Sci U S A
January 2025
Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype.
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