H3K27M Vaccine Appears Safe and Immunogenic in Diffuse Midline Glioma

Diffuse midline gliomas (DMG) are aggressive primary tumors of the central nervous system and often harbor a clonal driver mutation that leads to a lysine-to-methionine substitution of residue 27 in histone 3 (H3K27M). Given the low PD-L1 expression and the anatomic location of these tumors, the clinical benefit of immune checkpoint blockade or surgery remains limited. To examine whether an H3K27M-targeted vaccine strategy might elicit responses in H3K27M⁺ DMG, Grassl and colleagues administered a long H3K27M_14-40 peptide vaccine (H3K27M-vac) on a compassionate-use basis to eight adult patients with progressive H3K27M⁺ DMG previously treated with radiotherapy and chemotherapy. H3K27M-vac was administered via subcutaneous injection every 2 weeks for 6 weeks, followed by monthly administration for the next 4 months and quarterly administration until progressive disease, and five patients (62.5%) were concomitantly treated with anti–PD-1 based on their physician's discretion. A grade 1 injection site reaction related to H3K27M-vac was observed in two patients (25%), and no regimen-limiting toxicities were observed in any patients. H3K27M-specific immune responses elicited by vaccination were detected in the peripheral blood of five patients (62.5%), all of whom exhibited radiographic improvement shortly after the initial detection of an immune response. The median progression-free survival of eight patients after vaccination was 6.2 months, and median overall survival was 12.8 months. Notably, one patient, treated solely with H3K27M-vac, exhibited radiographic pseudoprogression after detection of an H3K27M-specific immune response and maintained complete remission for over 31 months. H3K27M-vac appeared capable of inducing responses across multiple human leukocyte antigen (HLA) types, as proximity ligation assay analysis of primary tumor tissues from seven patients revealed colocalization of H3K27M neoepitopes with HLA-DR molecules on tumor cells and antigen-presenting myeloid cells. Immune responses were largely driven by H3K27M-specific CD4⁺ T cells, with no discernable effect of H3K27M-vac on immunosuppressive regulatory T cells. In summary, these findings support the safety and immunogenicity of an H3K27M-targeted vaccination strategy and underscore the potential for clinical application in H3K27M⁺ DMG.

Grassl N, Poschke I, Lindner K, Bunse L, Mildenberger I, Boschert T, et al. A H3K27M-targeted vaccine in adults with diffuse midline glioma. Nat Med 2023 Sep 21 [Epub ahead of print].

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