A small first-in-human trial indicates that a vaccine targeting the histone H3 mutation H3K27M is safe and can induce a mutation-specific immune response in patients with diffuse midline glioma (DMG). Multiple doses of the vaccine were administered to eight adults with H3K27M+ DMG — an aggressive CNS tumour subtype that is currently incurable. The vaccine was well tolerated, and an H3K27M-specific immune response was detected in five of the participants. Induction of this response was associated with radiographic improvement, and one individual with a strong immune response showed sustained complete remission for more than 31 months.