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Journal Article

Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy

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Pecoraro,  Matteo
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Mann,  Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Chheda, Z. S., Kohanbash, G., Okada, K., Jahan, N., Sidney, J., Pecoraro, M., et al. (2018). Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy. Journal of Experimental Medicine, 215(1), 141-157. doi:10.1084/jem.20171046.


Cite as: https://hdl.handle.net/21.11116/0000-0000-74CE-6
Abstract
The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than one year. The majority of diffuse midline gliomas, including more than 70% of DIPGs, harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). From a CD8(+) T cell clone established by stimulation of HLA-A2(+) CD8(+) T cells with synthetic peptide encompassing the H3.3K27M mutation, complementary DNA for T cell receptor (TCR) alpha- and beta-chains were cloned into a retroviral vector. TCR -transduced HLA-A2(+) T cells efficiently killed HLA-A2(+)H3.3K27M(+) glioma cells in an antigen- and HLA-specific manner. Adoptive transfer of TCR -transduced T cells significantly suppressed the progression of glioma xenografts in mice. Alanine-scanning assays suggested the absence of known human proteins sharing the key amino acid residues required for recognition by the TCR, suggesting that the TCR could be safely used in patients. These data provide us with a strong basis for developing T cell-based therapy targeting this shared neoepitope.