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W4252002392 abstract "Brain cancers are the leading cause of cancer related mortality and morbidity in children and young adults. Children with diffuse intrinsic brainstem malignant gliomas have one-year progression-free survival rates below 25% and median overall survival of 9 to 10 months with current treatment options and hence represent a significant unmet medical need. Genome-wide sequencing efforts of pediatric gliomas have identified a recurrent and shared missense mutation in the gene encoding the replication-independent variant of histone 3, H3.3. Approximately 70% of diffuse intrinsic pontine gliomas (DIPG) and 50% of thalamic and other midline gliomas harbor the amino-acid substitution from lysine (K) to methionine (M) at the position 27 of H3.3 gene (H3.3.K27M mutation). Tumor-specific missense mutations are not subjected to self-tolerance and can be suitable targets (i.e. neoantigen) for cancer immunotherapy. We evaluated whether the H3.3.K27M mutation can induce specific cytotoxic T lymphocyte (CTL) response in HLA-A2+ human T cells. In vitro stimulation of HLA-A2+ donor-derived CD8+ T-cells with a synthetic peptide encompassing the H3.3.K27M mutation (H3.3.K27M epitope) induced CTL lines which recognized not only T2 cells loaded with the synthetic H3.3.K27M epitope peptide but also lysed HLA-A2+ DIPG cell lines which endogenously harbor the H3.3.K27M mutation. On the other hand, the CTL lines did not react to either HLA-A2+ H3.3.K27M -negative DIPG cell lines or H3.3K27M-positive but HLA-A2-negative cells. The H3.3.K27M epitope peptide, but not the non-mutant counterpart, indicated an excellent affinity (Kd 151nM) to HLA-A2 based on competitive binding inhibition assay. From CTL clones with high and specific affinities to HLA-A2-H3.3.K27M-tetramer, cDNAs for T cell receptor (TCR) α- and β-chains were cloned into a retroviral vector. Human HLA-A2+ T-cells transduced with the TCR demonstrated antigen-specific reactivity as well as anti-glioma responses in vitro. Peptide titration assay suggested that the H3.3.K27M-specific TCR had the half-maximal reactivity for peptide recognition of around 100nM. Furthermore, critically important for safety of clinical application, alanine scanning demonstrated that the key amino-acid sequence motif in the epitope for the TCR reactivity is not shared by any known human protein. Finally, intravenous administration of T-cells transduced with the H3.3.K27M-specific TCR significantly inhibited the growth of intracranial HLA-A2+ H3.3.K27M-positive glioma xenografts in immune-deficient mice. These data provide us with a strong basis for developing peptide-based vaccines as well as adoptive transfer therapy using autologous T-cells transduced with the H3.3.K27M-specific TCR." @default.
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W4252002392 date "2017-04-01" @default.
W4252002392 modified "2023-09-27" @default.
W4252002392 title "OS09.4 Identification of a novel H3.3.K27M mutation-derived neoantigen epitope and cloning of H3.3.K27M-specific T-cell receptor for T-cell therapy in gliomas" @default.
W4252002392 doi "https://doi.org/10.1093/neuonc/nox036.063" @default.
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