P01.140 An H3.3K27M long peptide vaccine induces expansion of specific CD4 and CD8 T cell clones in a patient with progressive H3.3K27M-mutant midline glioma. (19th September 2018)

• Record Type: Journal Article
• Authors: Sahm, K; Mildenberger, I; Bunse, L; Green, E; Wick, W; Platten, M
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 3
• Page Start: iii264
• Page End: iii264
• Publication Date: 2018-09-19
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy139.182
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Diffuse gliomas of the thalamus, brain stem, spinal cord or other midline structures represent a well-defined subgroup of high grade gliomas typically occurring in children and adolescents but also in adult patients. On a molecular level, diffuse midline gliomas harbor an amino acid exchange at position 27 of the histone-3 gene (H3.3K27M) as a characteristic driver mutation in > 70% of cases. We have previously demonstrated that a peptide vaccine encoding the H3.3K27M epitope induces a major histocompatibility complex (MHC) class I-restricted CD8 + T cell as well as an MHC class II-restricted CD4 + immune response. These immune responses effectively inhibited growth of H3.3K27M-overexpressing flank tumors in an MHC-humanized A2DR1 mouse model. Here, we show immune monitoring results of an HLA-A2 + patient with progressive H3.3K27M-mutant glioma vaccinated with an H3.3K27M long peptide emulsified in Montanide in combination with Nivolumab on a compassionate-use basis. Treatment was well tolerated and immunogenicity analyses of peripheral blood monocytes showed induction of a mutation-specific peripheral IFNγ immune response after four vaccines. Moreover, single CD8 + and CD4 + T cells specifically responding to H3.3K27M were expanded in vitro and subjected to single-cell-sorting and subsequent T cell receptor (TCR) sequencing. Here, 6 TCR clonotypes showing clear expansion after vaccination have been identified. TCR clonotypes were also assessed in CSF to evaluate mutation-specific immunity within the CNS. These data demonstrate immunogenicity of an H3.3K27M peptide vaccine inducing mutation-specific CD4 + and CD8 + T cells and pave the way for the development of adoptive T cell therapy for patients with H3.3K27M-mutant midline gliomas using TCR-transgenic T cells derived from vaccinated patients targeting the clonal H3.3K27M neoepitope.