Isocitrate dehydrogenase 1 (IDH1) R132H mutant neoepitope (IDH1 R132H neoepitope)

The IDH1 R132H mutant neoepitope is a tumor-specific antigen resulting from a recurrent somatic point mutation in the isocitrate dehydrogenase 1 (IDH1) enzyme, where arginine is substituted by histidine at residue 132. This mutation is a defining molecular feature of over 70% of lower-grade gliomas and secondary glioblastomas, and it also occurs in a subset of acute myeloid leukemia and chondrosarcoma cases (Platten et al., 2021, Nature). The mutation confers a neomorphic enzymatic activity that leads to the accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG), which drives oncogenesis through epigenetic dysregulation and DNA hypermethylation (Waitkus et al., 2018, Science Signaling). Crucially, the R132H substitution creates a novel peptide sequence that can be processed and presented by major histocompatibility complex (MHC) molecules, particularly HLA-DRB1*01:01, making it a highly specific target for immunotherapy (Schumacher et al., 2014, Nature). Therapeutic strategies include peptide-based vaccines designed to trigger mutation-specific T-cell responses and small molecule inhibitors that target the mutant enzyme's catalytic site to normalize cellular metabolism. Because the neoepitope is entirely absent in healthy tissues, it offers a high degree of therapeutic specificity and a favorable safety profile for precision oncology.

Other names

IDH1-R132H neoantigenMutant IDH1 R132H peptideIDH1 R132H mutation-derived epitopeIDH1R132H

The IDH1 R132H mutant neoepitope is targeted by immunotherapies, such as the IDH1-vac peptide vaccine, which induce mutation-specific CD4+ T-helper cell responses by presenting the mutant peptide on MHC class II molecules (Platten et al., 2021, Nature). Additionally, small molecule inhibitors like Ivosidenib and Vorasidenib target the mutant IDH1 protein itself, binding to the active site to inhibit the neomorphic production of the oncometabolite D-2-hydroxyglutarate (Mellinghoff et al., 2023, NEJM).