{"doi":"10.1136/jitc-2022-004644","title":"Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma","abstract":"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 R132H glioma model was created in syngeneic HLA-A2/HLA-DR1 -transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1 R132H 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 R132H peptide vaccination or anti-PD-1 immune checkpoint blockade. Results The HLA-A2/HLA-DR1 -syngeneic IDH1 R132H 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 R132H glioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1 R132H gliomas. AG-881 monotherapy suppressed the progression of IDH1 R132H 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 R132H peptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1 R132H and DR1-IDH1 R132H 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 R132H -targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our HLA-A2/HLA-DR1 -syngeneic IDH1 R132H glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.","journal":"Journal for ImmunoTherapy of Cancer","year":2022,"id":247218,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":748177,"name":"Akane Yamamichi","orcid":"0000-0002-8141-7339","position":1,"is_corresponding":false},{"id":557753,"name":"Tiffany Chen","orcid":"0000-0003-2549-7482","position":2,"is_corresponding":false},{"id":885253,"name":"Rohini Narayanaswamy","orcid":null,"position":3,"is_corresponding":false},{"id":884655,"name":"Sébastien Ronseaux","orcid":"0000-0002-4071-1451","position":4,"is_corresponding":false},{"id":885254,"name":"Christine C. 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