CAR-T cells for H3K27-altered diffuse midline gliomas: where do we stand?

Among the pediatric brain tumors, diffuse midline gliomas (DMG) harboring a mutation in histone H3K27 have the deadliest prognosis. These tumors are most commonly found in the midline structures of the brain resulting in cranial nerve palsies and diplopia at clinical presentation. Standard of care is radiation therapy although this is predominately palliative. At a molecular level, lysine (K) 27 is most commonly replaced by a methionine (M) but regardless of the specific histone H3 mutation, there is a global reduction in H3K27 trimethylation. This mutation most often occurs at one of two genes; most commonly the H3F3A gene resulting in the canonical H3.3K27M but also the HIST1H3B resulting in H3.1K27M. Although these tumors have a relatively low mutational burden in comparison to other cancers, other mutations contributing to tumoriogenesis have been documented including TP53 and PDGFRA, both of which are implicated in as driving mutations of proliferation in a variety of cancers. Over the decades, conventional chemotherapy and more recently, targeted agents have still failed to provide any survival benefit.