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 PMID:29203539  

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

Zinal S Chheda | Gary Kohanbash | Kaori Okada | Naznin Jahan | John Sidney | Matteo Pecoraro | Xinbo Yang | Diego A Carrera | Kira M Downey | Shruti Shrivastav | Shuming Liu | Yi Lin | Chetana Lagisetti | Pavlina Chuntova | Payal B Watchmaker | Sabine Mueller | Ian F Pollack | Raja Rajalingam | Angel M Carcaboso | Matthias Mann | Alessandro Sette | K Christopher Garcia | Yafei Hou | Hideho Okada
The Journal of experimental medicine | 2018

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) α- and β-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.

Pubmed ID: 29203539

Associated grants

  • Agency: NINDS NIH HHS, United States
    Id: R01 NS055140
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS096954
  • Agency: NINDS NIH HHS, United States
    Id: R35 NS105068
  • Agency: NCI NIH HHS, United States
    Id: T32 CA151022

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