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A vaccine targeting mutant IDH1 in newly diagnosed glioma

Platten, Michael ; Bunse, Lukas ; Wick, Antje ; Bunse, Theresa ; Le Cornet, Lucian ; Harting, Inga ; Sahm, Felix ; Sanghvi, Khwab ; Tan, Chin Leng ; Poschke, Isabel ; Green, Edward ; Justesen, Sune ; Behrens, Geoffrey A ; Breckwoldt, Michael O ; Freitag, Angelika ; Rother, Lisa-Marie ; Schmitt, Anita ; Schnell, Oliver ; Hense, Jörg ; Misch, Martin ; Krex, Dietmar ; Stevanovic, Stefan ; Tabatabai, Ghazaleh ; Steinbach, Joachim P ; Bendszus, Martin ; von Deimling, Andreas ; Schmitt, Michael ; Wick, Wolfgang

Nature (London), 2021-04, Vol.592 (7854), p.463-468 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
A vaccine targeting mutant IDH1 in newly diagnosed glioma
Autor: Platten, Michael ; Bunse, Lukas ; Wick, Antje ; Bunse, Theresa ; Le Cornet, Lucian ; Harting, Inga ; Sahm, Felix ; Sanghvi, Khwab ; Tan, Chin Leng ; Poschke, Isabel ; Green, Edward ; Justesen, Sune ; Behrens, Geoffrey A ; Breckwoldt, Michael O ; Freitag, Angelika ; Rother, Lisa-Marie ; Schmitt, Anita ; Schnell, Oliver ; Hense, Jörg ; Misch, Martin ; Krex, Dietmar ; Stevanovic, Stefan ; Tabatabai, Ghazaleh ; Steinbach, Joachim P ; Bendszus, Martin ; von Deimling, Andreas ; Schmitt, Michael ; Wick, Wolfgang
Assuntos: Adult ; Adverse events ; Antigens ; Astrocytoma ; Cancer ; Cancer vaccines ; Cancer Vaccines - immunology ; Cancer Vaccines - therapeutic use ; Care and treatment ; Cells, Cultured ; Combined vaccines ; CXCL13 protein ; Cytokines ; Development and progression ; Disease Progression ; Female ; Gene sequencing ; Genetic aspects ; Glioma ; Glioma - diagnosis ; Glioma - genetics ; Glioma - immunology ; Glioma - therapy ; Gliomas ; Health aspects ; Helper cells ; Humans ; Immune response ; Immune system ; Inflammation ; Isocitrate dehydrogenase ; Isocitrate Dehydrogenase - genetics ; Isocitrate Dehydrogenase - immunology ; Lymphocytes ; Lymphocytes T ; Major histocompatibility complex ; Male ; Mutant Proteins - genetics ; Mutant Proteins - immunology ; Mutation ; Neoantigens ; Oxidoreductases ; Patients ; Peptides ; Phenotype ; Physiological aspects ; Pretreatment ; Radiation therapy ; Receptors ; Receptors, Antigen, T-Cell - immunology ; Survival Rate ; T cell receptors ; T cells ; T-Lymphocytes - immunology ; Testing ; Tumor necrosis factor-TNF ; Tumors ; Vaccines ; Working groups
É parte de: Nature (London), 2021-04, Vol.592 (7854), p.463-468
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma . The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II . An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H) tumours in syngeneic MHC-humanized mice . Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H) astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG and CXCL13 T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.
Editor: England: Nature Publishing Group
Idioma: Inglês

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A vaccine targeting mutant IDH1 in newly diagnosed glioma

England: Nature Publishing Group

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