H3.3K27M-specific T cell receptor (H3.3K27M-specific TCR)

The H3.3K27M-specific T cell receptor (TCR) is an engineered or naturally occurring immune receptor designed to target a specific neoantigen found in diffuse midline gliomas (DMG) (Chheda et al., 2018, Nature). This neoantigen arises from a recurrent mutation in the H3F3A gene, substituting lysine with methionine at position 27 of histone H3.3, which drives oncogenesis by altering chromatin states. The TCR specifically recognizes the H3.3K27M peptide sequence presented by major histocompatibility complex (MHC) molecules, such as HLA-A*02:01 for CD8+ T cells or MHC class II for CD4+ T cells (Ochs et al., 2017, Clin Cancer Res). Upon recognition, the TCR-engineered T cells initiate a targeted immune response, including the secretion of interferon-gamma and direct lysis of tumor cells (Chheda et al., 2018, Nature). This approach is currently being explored in clinical trials using adoptive cell transfer to treat pediatric patients with DIPG and other midline gliomas (Mueller et al., 2020, J Clin Oncol). Therapeutic efficacy depends on the successful infiltration of these T cells into the central nervous system and the persistence of the H3.3K27M mutation within the tumor mass. Safety considerations include potential neuro-inflammation and the risk of off-target effects if the TCR cross-reacts with wild-type histone proteins.

Other names

Histone H3.3 K27M-specific T-cell receptorH3.3K27M-reactive TCRH3.3K27M-targeted TCRH3.3K27M-specific T-cell receptor on CD8+ and CD4+ T cells

Recognition of the H3.3K27M neoantigen peptide presented by HLA molecules (e.g., HLA-A*02:01) on tumor cells, triggering T-cell activation and targeted lysis of the malignant cells.