(1) Grassl N (2) Poschke I (3) Lindner K (4) Bunse L (5) Mildenberger I (6) Boschert T (7) Jähne K (8) Green EW (9) Hülsmeyer I (10) Jünger S (11) Kessler T (12) Suwala AK (13) Eisele P (14) Breckwoldt MO (15) Vajkoczy P (16) Grauer OM (17) Herrlinger U (18) Tonn JC (19) Denk M (20) Sahm F (21) Bendszus M (22) von Deimling A (23) Winkler F (24) Wick W (25) Platten M (26) Sahm K

Nature medicine

Grassl et al. report the safe first-in-human compassionate use of s.c. vaccination with a long peptide targeting the driver mutation in histone 3 (H3K27M) in eight adult patients with aggressive H3K27M+ diffuse midline glioma. Five of the patients received H3K27M-vac + anti-PD-1. Upon repeated treatments, mutation-specific immune responses, dominated by CD4+ T cells, were induced in five of eight patients of various HLA types. Median PFS was 6.2 months; median OS was 12.8 months. One patient who had not received anti-PD-1, but had a strong mutation-specific T cell response exhibited pseudoprogression and then complete remission for >31 months.

Contributed by Paula Hochman

Substitution of lysine 27 to methionine in histone H3 (H3K27M) defines an aggressive subtype of diffuse glioma. Previous studies have shown that a H3K27M-specific long peptide vaccine (H3K27M-vac) induces mutation-specific immune responses that control H3K27M(+) tumors in major histocompatibility complex-humanized mice. Here we describe a first-in-human treatment with H3K27M-vac of eight adult patients with progressive H3K27M(+) diffuse midline glioma on a compassionate use basis. Five patients received H3K27M-vac combined with anti-PD-1 treatment based on physician's discretion. Repeat vaccinations with H3K27M-vac were safe and induced CD4(+) T cell-dominated, mutation-specific immune responses in five of eight patients across multiple human leukocyte antigen types. Median progression-free survival after vaccination was 6.2 months and median overall survival was 12.8 months. One patient with a strong mutation-specific T cell response after H3K27M-vac showed pseudoprogression followed by sustained complete remission for >31 months. Our data demonstrate safety and immunogenicity of H3K27M-vac in patients with progressive H3K27M(+) diffuse midline glioma.

Author Info: (1) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelb

Author Info: (1) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany. DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany. (2) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Immune Monitoring Unit, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. (3) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Immune Monitoring Unit, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. (4) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany. DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany. (5) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany. DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany. (6) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Immune Monitoring Unit, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. Helmholtz Institute for Translational Oncology (HI-TRON) Mainz, German Cancer Research Center, Mainz, Germany. (7) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany. DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany. (8) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany. DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany. (9) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Immune Monitoring Unit, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. (10) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Immune Monitoring Unit, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. (11) Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany. National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. (12) Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany. DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (13) Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany. (14) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany. Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany. (15) Department of Neurosurgery, CharitŽ-UniversitŠtsmedizin Berlin, Berlin, Germany. (16) Department of Neurology with Institute of Translational Neurology, University of MŸnster, MŸnster, Germany. (17) Division of Clinical Neurooncology, Department of Neurology, University Hospital Bonn, University of Bonn, Bonn, Germany. (18) Department of Neurosurgery, University of Munich LMU, Munich, Germany. (19) Institute of Cell Biology, Department of Immunology, University of TŸbingen, TŸbingen, Germany. (20) Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany. DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (21) Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany. (22) Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany. DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (23) Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany. National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. (24) Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany. National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. (25) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.platten@dkfz-heidelberg.de. Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany. m.platten@dkfz-heidelberg.de. DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany. m.platten@dkfz-heidelberg.de. Immune Monitoring Unit, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. m.platten@dkfz-heidelberg.de. Helmholtz Institute for Translational Oncology (HI-TRON) Mainz, German Cancer Research Center, Mainz, Germany. m.platten@dkfz-heidelberg.de. (26) DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. k.sahm@dkfz-heidelberg.de. Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany. k.sahm@dkfz-heidelberg.de. DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany. k.sahm@dkfz-heidelberg.de.

Citation: Nat Med 2023 Sep 21 Epub09/21/2023

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/37735561

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