Boschert, Kromer, and Lerner et al. conducted an in-depth analysis of a midline glioma patient who experienced a complete response following vaccination with a long peptide encoding the H3K27M driver mutation. The T cell response was dominated by polyclonal, antigen-specific CD4+ cells restricted by relatively common alleles. Longitudinal β-chain analysis of paired αβ clonotypes demonstrated dramatic expansion in the blood and overlap of some clonotypes in CSF, the latter of which had a central memory phenotype. CSF also contained populations of memory B cells and permablasts with BCR specificity directed toward H3K27M peptides and proteins.
Contributed by Ed Fritsch
ABSTRACT: H3K27M, a driver mutation with T and B cell neoepitope characteristics, defines an aggressive subtype of diffuse glioma with poor survival. We functionally dissect the immune response of one patient treated with an H3K27M peptide vaccine who subsequently entered complete remission. The vaccine robustly expanded class II human leukocyte antigen (HLA)-restricted peripheral H3K27M-specific T cells. Using functional assays, we characterized 34 clonally unique H3K27M-reactive T cell receptors and identified critical, conserved motifs in their complementarity-determining region 3 regions. Using detailed HLA mapping, we further demonstrate that diverse HLA-DQ and HLA-DR alleles present immunogenic H3K27M epitopes. Furthermore, we identified and profiled H3K27M-reactive B cell receptors from activated B cells in the cerebrospinal fluid. Our results uncover the breadth of the adaptive immune response against a shared clonal neoantigen across multiple HLA allelotypes and support the use of class II-restricted peptide vaccines to stimulate tumor-specific T and B cells harboring receptors with therapeutic potential.
Author Info: (1) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. H
Author Info: (1) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. Helmholtz Institute for Translational Oncology (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ, Mainz, Germany. (2) Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. BioMed X GmbH, Heidelberg, Germany. (3) BioMed X GmbH, Heidelberg, Germany. (4) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. Immune Monitoring Unit, DKFZ and National Center for Tumour Diseases (NCT), Heidelberg, Germany. (5) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (6) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (7) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (8) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Immune Monitoring Unit, DKFZ and National Center for Tumour Diseases (NCT), Heidelberg, Germany. (9) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN Heidelberg University, Mannheim, Germany. (10) Department of Neurology, Medical Faculty Mannheim, MCTN Heidelberg University, Mannheim, Germany. (11) Department of Neurology, Medical Faculty Mannheim, MCTN Heidelberg University, Mannheim, Germany. (12) Department of Neurology, Medical Faculty Mannheim, MCTN Heidelberg University, Mannheim, Germany. (13) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN Heidelberg University, Mannheim, Germany. (14) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Helmholtz Institute for Translational Oncology (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ, Mainz, Germany. Immune Monitoring Unit, DKFZ and National Center for Tumour Diseases (NCT), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN Heidelberg University, Mannheim, Germany. DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim Germany. (15) BioMed X GmbH, Heidelberg, Germany. (16) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN Heidelberg University, Mannheim, Germany.
