Mueller and Taitt et al. reported the safety and efficacy of an H3.3K27M-targeted peptide vaccine in patients with HLA-A*02:01+H3.3K27M+ diffuse midline gliomas (Stratum A) and diffuse intrinsic pontine glioma (Stratum B). The treatment was well tolerated with an OS of 44% for Stratum A and 39% for Stratum B at 12 months. Immunological responders (expansion of H3.3K27M-reactive CD8+ T cells) demonstrated an improved OS of 16.1 months compared to 9.8 months for non-responders. High myeloid-derived suppressor cells (MDSChi) or dexamethasone pretreatment showed inverse association with survival.
Contributed by Shishir Pant
BACKGROUND: Patients with diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+ H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed safety and efficacy of an H3.3K27M-targeted peptide vaccine. PATIENTS AND METHODS: Newly diagnosed patients aged 3-21 years with HLA-A*02.01+ and H3.3K27M+ status were enrolled into Stratum A (DIPG) and Stratum B (non-pontine DMG). Vaccine was administered in combination with poly-ICLC every three weeks for eight cycles, followed by once every six weeks. Immuno-monitoring and imaging occurred every three months. Imaging was centrally reviewed. Immunological responses were assessed in peripheral blood mononuclear cells using mass cytometry. RESULTS: 19 patients enrolled in Stratum A (median age=11 years) and 10 in Stratum B (median age=13 years). There were no grade 4 treatment-related adverse events (TRAE). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22% to 73%) for Stratum A and 39% (95% CI, 16% to 93%) for Stratum B. The median OS was 16.1 months in patients exhibiting an expansion of H3.3K27M-reactive CD8+ T-cells compared to 9.8 months for their counterparts (p=0.05). DIPG patients with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared to their counterparts (p<0.01). Immediate pre-treatment dexamethasone administration inversely associated with H3.3K27M-reactive CD8+ T-cell responses. CONCLUSION: Administration of the H3.3K27M-specific vaccine is well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared to non-responders.