Henning Zelba1<\/sup>, Borong Shao1<\/sup>, Armin Rabsteyn1<\/sup>, Annekathrin Reinhardt1<\/sup>, Carsten Greve1<\/sup>, Lisa Oenning1<\/sup>, Simone Kayser1<\/sup>, Christina Kyzirakos1<\/sup>, Pauline Latzer1<\/sup>, Tabea Riedlinger1<\/sup>, Oliver Bartsch1<\/sup>, Julian W\u00fcnsche2<\/sup>, Johannes Harter3<\/sup>, Magdalena Feldhahn3<\/sup>, Yannick Bantel3<\/sup>, Janina Joh\u00e4nning3<\/sup>, Jiri K\u00f6dding3<\/sup>, Dirk Hadaschik4<\/sup>, Martin Schulze1<\/sup>, Florian Battke3<\/sup>, Olga Maksimovic2<\/sup>, Veit Scheble2<\/sup>, Alexandra M Miller5<\/sup>, Michael Castro6,7<\/sup>, Deborah T Blumenthal8<\/sup>, Martin Glas9<\/sup>, David Reardon10<\/sup>\u00a0and Saskia Biskup1,2,3,4<\/sup><\/p>\n<\/div><\/div><\/div><\/div><\/div> Isocitrate dehydrogenase (IDH) mutant glioma is a malignant primary brain tumor diagnosed in adults. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors. The first targeted IDH-inhibitor was approved by the US Food and Drug Administration in August 2024 for grade 2 gliomas, in light of results of a phase III trial which showed significant advantages in progression-free survival. However, biologic therapy is not curative, and subsequent treatment options offer only limited clinical benefit and often result in long-term toxicities. In addition, targeted treatment options for grade 3 and grade 4 IDH-mutant gliomas are still missing. In this study, we present n=52 patients with glioma (grade 2, 3 and 4) with confirmed IDH1 mutation (mutIDH1) in the newly diagnosed and recurrent setting who, in addition to standard-of-care, received a personalized neoantigen-targeting peptide vaccine. Each tumor was initially analyzed for somatic mutations by whole exome sequencing, and a peptide vaccine containing potential neoepitopes was designed, manufactured and vaccinated. Each vaccine consisted of peptides derived from numerous somatic mutations, including at least one peptide targeting the mutIDH1.<\/p>\n Vaccine immunogenicity was determined by intracellular cytokine staining and simultaneous measurement of four T-cell activation markers (Interferon-\u03b3, Tumor Necrosis Factor, Interleukin-2, CD154) after 12-day in vitro expansion of pre and post vaccination peripheral blood mononuclear cells. Extracellular CD154 staining was used to sort mutIDH1-specific CD4+T cells.<\/p>\n Immunomonitoring revealed that the vaccines were immunogenic and induced mainly CD4 but also CD8 T cell responses. Vaccine-induced immune responses were robust and polyfunctional. Immunogenicity against mutIDH1 was high (89%). We implemented an assay which allowed us to isolate functional antigen-specific CD4+T cells in an HLA-independent manner. Subsequent T cell receptor (TCR) repertoire sequencing revealed that CD4+T cells reacting on mutIDH1 stimulation were polyclonal. Strikingly, we detected two mutIDH1-specific TCR\u03b2 candidate sequences in three different patients. These three patients had the same human leukocyte antigen (HLA) DQA-DQB alleles. The obtained TCR\u03b2 sequences could be tracked in autologous ex-vivo single-cell transcriptomic data. Our results provide a rationale for pursuing vaccination and T cell transfer strategies targeting IDH1. Furthermore, our findings indicate that personalized neoantigen-targeting vaccines might be considered for the treatment of IDH1-mutant gliomas.<\/p>\n Keywords: <\/strong>T cell; T cell Receptor – TCR; Vaccine.<\/p>\n<\/div><\/div><\/div><\/div><\/div>Abstract<\/h2><\/div><\/div><\/div>
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