DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany.
Nat Med. 2023 Oct;29(10):2586-2592. doi: 10.1038/s41591-023-02555-6. Epub 2023 Sep 21.
Substitution of lysine 27 to methionine in histone H3 (H3K27M) defines an aggressive subtype of diffuse glioma. Previous studies have shown that a H3K27M-specific long peptide vaccine (H3K27M-vac) induces mutation-specific immune responses that control H3K27M tumors in major histocompatibility complex-humanized mice. Here we describe a first-in-human treatment with H3K27M-vac of eight adult patients with progressive H3K27M diffuse midline glioma on a compassionate use basis. Five patients received H3K27M-vac combined with anti-PD-1 treatment based on physician's discretion. Repeat vaccinations with H3K27M-vac were safe and induced CD4 T cell-dominated, mutation-specific immune responses in five of eight patients across multiple human leukocyte antigen types. Median progression-free survival after vaccination was 6.2 months and median overall survival was 12.8 months. One patient with a strong mutation-specific T cell response after H3K27M-vac showed pseudoprogression followed by sustained complete remission for >31 months. Our data demonstrate safety and immunogenicity of H3K27M-vac in patients with progressive H3K27M diffuse midline glioma.
赖氨酸 27 突变为蛋氨酸的组蛋白 H3（H3K27M）定义了弥漫性神经胶质瘤的侵袭性亚型。先前的研究表明，H3K27M 特异性长肽疫苗（H3K27M-vac）可诱导突变特异性免疫反应，从而控制主要组织相容性复合体人源化小鼠中的 H3K27M 肿瘤。在此，我们描述了在同情使用的基础上，用 H3K27M-vac 治疗 8 名进展性 H3K27M 弥漫性中线神经胶质瘤的成年患者的首例人体治疗。根据医生的判断，5 名患者接受了 H3K27M-vac 联合抗 PD-1 治疗。重复接种 H3K27M-vac 是安全的，并在 8 名患者中的 5 名中诱导了 CD4 T 细胞为主的、针对突变的免疫反应，跨越多种人类白细胞抗原类型。接种疫苗后的无进展生存期中位数为 6.2 个月，总生存期中位数为 12.8 个月。1 名患者在接受 H3K27M-vac 治疗后出现强烈的突变特异性 T 细胞反应，随后出现假性进展，持续完全缓解超过 31 个月。我们的数据表明，H3K27M-vac 在进展性 H3K27M 弥漫性中线神经胶质瘤患者中是安全且具有免疫原性的。
