INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomas
Abstract Introduction Diffuse midline gliomas (DMG) are universally lethal central nervous system tumors that carry almost unanimously the clonal driver mutation histone-3 K27M (H3K27M). The single amino acid substitution of lysine to methionine harbors a neoantigen that is presented in tumor tissue...
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Neurological Research and Practice |
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| Online Access: | https://doi.org/10.1186/s42466-023-00282-4 |
| _version_ | 1797555538250170368 |
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| author | Niklas Grassl Katharina Sahm Heike Süße Isabel Poschke Lukas Bunse Theresa Bunse Tamara Boschert Iris Mildenberger Anne-Kathleen Rupp Max Philipp Ewinger Lisa-Marie Lanz Monika Denk Ghazaleh Tabatabai Michael W. Ronellenfitsch Ulrich Herrlinger Martin Glas Dietmar Krex Peter Vajkoczy Antje Wick Inga Harting Felix Sahm Andreas von Deimling Martin Bendszus Wolfgang Wick Michael Platten |
| author_facet | Niklas Grassl Katharina Sahm Heike Süße Isabel Poschke Lukas Bunse Theresa Bunse Tamara Boschert Iris Mildenberger Anne-Kathleen Rupp Max Philipp Ewinger Lisa-Marie Lanz Monika Denk Ghazaleh Tabatabai Michael W. Ronellenfitsch Ulrich Herrlinger Martin Glas Dietmar Krex Peter Vajkoczy Antje Wick Inga Harting Felix Sahm Andreas von Deimling Martin Bendszus Wolfgang Wick Michael Platten |
| author_sort | Niklas Grassl |
| collection | DOAJ |
| description | Abstract Introduction Diffuse midline gliomas (DMG) are universally lethal central nervous system tumors that carry almost unanimously the clonal driver mutation histone-3 K27M (H3K27M). The single amino acid substitution of lysine to methionine harbors a neoantigen that is presented in tumor tissue. The long peptide vaccine H3K27M-vac targeting this major histocompatibility complex class II (MHC class II)-restricted neoantigen induces mutation-specific immune responses that suppress the growth of H3K27M+ flank tumors in an MHC-humanized rodent model. Methods INTERCEPT H3 is a non-controlled open label, single arm, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of H3K27M-vac in combination with standard radiotherapy and the immune checkpoint inhibitor atezolizumab (ATE). 15 adult patients with newly diagnosed K27M-mutant histone-3.1 (H3.1K27M) or histone-3.3 (H3.3K27M) DMG will be enrolled in this trial. The 27mer peptide vaccine H3K27M-vac will be administered concomitantly to standard radiotherapy (RT) followed by combinatorial treatment with the programmed death‐ligand 1 (PD-L1) targeting antibody ATE. The first three vaccines will be administered bi-weekly (q2w) followed by a dose at the beginning of recovery after RT and six-weekly administrations of doses 5 to 11 thereafter. In a safety lead-in, the first three patients (pts. 1–3) will be enrolled sequentially. Perspective H3K27M-vac is a neoepitope targeting long peptide vaccine derived from the clonal driver mutation H3K27M in DMG. The INTERCEPT H3 trial aims at demonstrating (1) safety and (2) immunogenicity of repeated fixed dose vaccinations of H3K27M-vac administered with RT and ATE in adult patients with newly diagnosed H3K27M-mutant DMG. Trial registration NCT04808245. |
| first_indexed | 2024-03-10T16:48:56Z |
| format | Article |
| id | doaj.art-968882c501c548889b7af8e6c08a2e21 |
| institution | Directory Open Access Journal |
| issn | 2524-3489 |
| language | English |
| last_indexed | 2024-03-10T16:48:56Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Neurological Research and Practice |
| spelling | doaj.art-968882c501c548889b7af8e6c08a2e212023-11-20T11:22:50ZengBMCNeurological Research and Practice2524-34892023-10-01511610.1186/s42466-023-00282-4INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomasNiklas Grassl0Katharina Sahm1Heike Süße2Isabel Poschke3Lukas Bunse4Theresa Bunse5Tamara Boschert6Iris Mildenberger7Anne-Kathleen Rupp8Max Philipp Ewinger9Lisa-Marie Lanz10Monika Denk11Ghazaleh Tabatabai12Michael W. Ronellenfitsch13Ulrich Herrlinger14Martin Glas15Dietmar Krex16Peter Vajkoczy17Antje Wick18Inga Harting19Felix Sahm20Andreas von Deimling21Martin Bendszus22Wolfgang Wick23Michael Platten24Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZClinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZNational Center for Tumor Diseases (NCT) Trial Center, NCTClinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZClinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZClinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZClinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZClinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZNational Center for Tumor Diseases (NCT) Trial Center, NCTNational Center for Tumor Diseases (NCT) Trial Center, NCTNational Center for Tumor Diseases (NCT) Trial Center, NCTDepartment of Peptide-based Immunotherapy, University and University Hospital TübingenDepartment of Neurology & Neuro-Oncology, University Hospital TübingenDr. Senckenberg Institute for Neurooncology, University Hospital FrankfurtDivision of Clinical Neurooncology, University Hospital BonnDivision of Clinical Neurooncology, Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS) and West German Cancer Center, Partner Site Essen, University Hospital Essen, German Cancer Consortium, University Duisburg-EssenClinic and Polyclinic for Neurosurgery, University Hospital Carl Gustav Carus DresdenDepartment of Neurosurgery, Charité BerlinDepartment of Neurology, University Hospital HeidelbergDepartment of Neuroradiology, Heidelberg University HospitalDepartment of Neuropathology, University Hospital HeidelbergDepartment of Neuropathology, University Hospital HeidelbergDepartment of Neuroradiology, Heidelberg University HospitalDepartment of Neurology, University Hospital HeidelbergClinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZAbstract Introduction Diffuse midline gliomas (DMG) are universally lethal central nervous system tumors that carry almost unanimously the clonal driver mutation histone-3 K27M (H3K27M). The single amino acid substitution of lysine to methionine harbors a neoantigen that is presented in tumor tissue. The long peptide vaccine H3K27M-vac targeting this major histocompatibility complex class II (MHC class II)-restricted neoantigen induces mutation-specific immune responses that suppress the growth of H3K27M+ flank tumors in an MHC-humanized rodent model. Methods INTERCEPT H3 is a non-controlled open label, single arm, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of H3K27M-vac in combination with standard radiotherapy and the immune checkpoint inhibitor atezolizumab (ATE). 15 adult patients with newly diagnosed K27M-mutant histone-3.1 (H3.1K27M) or histone-3.3 (H3.3K27M) DMG will be enrolled in this trial. The 27mer peptide vaccine H3K27M-vac will be administered concomitantly to standard radiotherapy (RT) followed by combinatorial treatment with the programmed death‐ligand 1 (PD-L1) targeting antibody ATE. The first three vaccines will be administered bi-weekly (q2w) followed by a dose at the beginning of recovery after RT and six-weekly administrations of doses 5 to 11 thereafter. In a safety lead-in, the first three patients (pts. 1–3) will be enrolled sequentially. Perspective H3K27M-vac is a neoepitope targeting long peptide vaccine derived from the clonal driver mutation H3K27M in DMG. The INTERCEPT H3 trial aims at demonstrating (1) safety and (2) immunogenicity of repeated fixed dose vaccinations of H3K27M-vac administered with RT and ATE in adult patients with newly diagnosed H3K27M-mutant DMG. Trial registration NCT04808245.https://doi.org/10.1186/s42466-023-00282-4GliomaCentral nervous system tumorDiffuse midline gliomaT cellVaccineAntigen |
| spellingShingle | Niklas Grassl Katharina Sahm Heike Süße Isabel Poschke Lukas Bunse Theresa Bunse Tamara Boschert Iris Mildenberger Anne-Kathleen Rupp Max Philipp Ewinger Lisa-Marie Lanz Monika Denk Ghazaleh Tabatabai Michael W. Ronellenfitsch Ulrich Herrlinger Martin Glas Dietmar Krex Peter Vajkoczy Antje Wick Inga Harting Felix Sahm Andreas von Deimling Martin Bendszus Wolfgang Wick Michael Platten INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomas Neurological Research and Practice Glioma Central nervous system tumor Diffuse midline glioma T cell Vaccine Antigen |
| title | INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomas |
| title_full | INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomas |
| title_fullStr | INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomas |
| title_full_unstemmed | INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomas |
| title_short | INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomas |
| title_sort | intercept h3 a multicenter phase i peptide vaccine trial for the treatment of h3 mutated diffuse midline gliomas |
| topic | Glioma Central nervous system tumor Diffuse midline glioma T cell Vaccine Antigen |
| url | https://doi.org/10.1186/s42466-023-00282-4 |
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