限于 HLA-A∗02:01 的内源性 H3.3K27M 衍生肽不足以在弥漫性中线胶质瘤中实现免疫靶向

Diffuse midline glioma (DMG) is a childhood brain tumor with an extremely poor prognosis. Chimeric antigen receptor (CAR) T cell therapy has recently demonstrated some success in DMG, but there may a need to target multiple tumor-specific targets to avoid antigen escape.

We developed a second-generation CAR targeting an HLA-A 02:01 restricted histone 3K27M epitope in DMG, the target of previous peptide vaccination and T cell receptor-mimics. These CAR T cells demonstrated specific, titratable, binding to cells pulsed with the H3. 3K27M peptide.

However, we were unable to observe scFv binding, CAR T cell activation, or cytotoxic function against H3. 3K27M + patient-derived models. Despite using sensitive immunopeptidomics, we could not detect the H3. 3K27M 26-35 -HLA-A 02:01 peptide on these patient-derived models.

Interestingly, other non-mutated peptides from DMG were detected bound to HLA-A 02:01 and other class I molecules, including a novel HLA-A3-restricted peptide encompassing the K27M mutation and overlapping with the H3 K27M 26-35 -HLA-A 02:01 peptide. These results suggest that targeting the H3 K27M 26-35 mutation in context of HLA-A 02:01 may not be a feasible immunotherapy strategy because of its lack of presentation.

These findings should inform future investigations and clinical trials in DMG.