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

Abstract

Chheda et al. have identified an HLA-A2–restricted CD8 ⁺ T cell epitope encompassing the H3.3K27M mutation and a corresponding TCR that specifically recognizes the H3.3K27M epitope in glioma cells. These data establish a preclinical basis for T cell–based therapy for HLA-A2 ⁺ patients with H3.3K27M ⁺ glioma.

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) 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.