AMPLIFY-NEOVAC: a randomized, 3-arm multicenter phase I trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with an immune checkpoint inhibitor targeting programmed death-ligand 1 in isocitrate dehydrogenase 1 mutant gliomas

Article

作者: Poschke, Isabel ; Gempt, Jens ; Platten, Michael ; Bendszus, Martin ; Steinbach, Joachim P ; Schnell, Oliver ; Bunse, Lukas ; Wuchter, Patrick ; Reifenberger, Guido ; Misch, Martin ; Rupp, Anne-Kathleen ; Bunse, Theresa ; Tabatabai, Ghazaleh ; Wick, Antje ; Glas, Martin ; Wick, Wolfgang ; Denk, Monika ; Blobner, Jens ; Lindner, Katharina

AbstractIntroductionIsocitrate dehydrogenase (IDH) mutations are disease-defining mutations in IDH-mutant astrocytomas and IDH-mutant and 1p/19q-codeleted oligodendrogliomas. In more than 80% of these tumors, point mutations in IDH type 1 (IDH1) lead to expression of the tumor-specific protein IDH1R132H. IDH1R132H harbors a major histocompatibility complex class II (MHCII)-restricted neoantigen that was safely and successfully targeted in a first-in human clinical phase 1 trial evaluating an IDH1R132H 20-mer peptide vaccine (IDH1-vac) in newly diagnosed astrocytomas concomitant to standard of care (SOC). MethodsAMPLIFY-NEOVAC is a randomized, 3-arm, window-of-opportunity, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with avelumab (AVE), an immune checkpoint inhibitor (ICI) targeting programmed death-ligand 1 (PD-L1). The target population includes patients with resectable IDH1R132H-mutant recurrent astrocytoma or oligodendroglioma after SOC. Neoadjuvant and adjuvant immunotherapy will be administered to 48 evaluable patients. In arm 1, 12 patients will receive IDH1-vac; in arm 2, 12 patients will receive the combination of IDH1-vac and AVE, and in arm 3, 24 patients will receive AVE only. Until disease progression according to immunotherapy response assessment for neuro-oncology (iRANO) criteria, treatment will be administered over a period of maximum 43 weeks (primary treatment phase) followed by facultative maintenance treatment.PerspectiveIDH1R132H 20-mer peptide is a shared clonal driver mutation-derived neoepitope in diffuse gliomas. IDH1-vac safely targets IDH1R132H in newly diagnosed astrocytomas. AMPLIFY-NEOVAC aims at (1) demonstrating safety of enhanced peripheral IDH1-vac-induced T cell responses by combined therapy with AVE compared to IDH1-vac only and (2) investigating intra-glioma abundance and phenotypes of IDH1-vac induced T cells in exploratory post-treatment tissue analyses. In an exploratory analysis, both will be correlated with clinical outcome.Trial registrationNCT03893903.

2021-08-01·ESMO Open3区 · 医学

Emerging targets for anticancer vaccination: IDH

3区 · 医学

ReviewOA

作者: M. Platten ; W. Wick ; L. Bunse

The development of anticancer vaccines as a pillar of cancer immunotherapy has been hampered by the scarcity of suitable tumor-specific antigens. While response to immune checkpoint inhibitors is driven by T cells recognizing mutated antigens, the vast majority of these neoantigens are patient-specific, mandating personalized approaches. In addition, neoantigens are often subclonal present in only a fraction of tumor cells resulting in immune evasion of neoantigen-negative tumor cells. Isocitrate dehydrogenase (IDH)1 mutations, most frequently encoding for the neomorphic protein IDH1R132H, are frequent driver mutations found in the majority of diffuse World Health Organization grade 2 and 3 gliomas. In addition, IDH1R132H generates a shared clonal neoepitope that is recognized by mutation-specific T-helper cells. A recent phase 1 trial (NOA-16, NCT02454634) demonstrated safety and immunogenicity of IDH1-vac, a long IDH1R132H peptide vaccine in patients with newly diagnosed astrocytoma and provided evidence of biological efficacy based on imaging parameters. In addition, vaccine-induced IDH1R132H-reactive tumor-infiltrating T cells were identified. Here we discuss clinical and scientific implications and future developments of IDH-directed immunotherapies.

2020-02-01·Journal of Neuro-Oncology2区 · 医学

Extracellular glutamate and IDH1R132H inhibitor promote glioma growth by boosting redox potential

2区 · 医学

Article

作者: Huang, L Eric ; Tiburcio, Patricia D B ; Gillespie, David L ; Jensen, Randy L

PURPOSESomatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, mostly substituting Arg132 with histidine, are associated with better patient survival, but glioma recurrence and progression are nearly inevitable, resulting in disproportionate morbidity and mortality. Our previous studies demonstrated that in contrast to hemizygous IDH1^R132H (loss of wild-type allele), heterozygous IDH1^R132H is intrinsically glioma suppressive but its suppression of three-dimensional (3D) growth is negated by extracellular glutamate and reducing equivalent. This study sought to understand the importance of 3D culture in IDH1^R132H biology and the underlying mechanism of the glutamate effect.METHODSRNA sequencing data of IDH1^R132H-heterozygous and IDH1^R132H-hemizygous glioma cells cultured under two-dimensional (2D) and 3D conditions were subjected to unsupervised hierarchal clustering and gene set enrichment analysis. IDH1^R132H-heterozygous and IDH1^R132H-hemizygous tumor growth were compared in subcutaneous and intracranial transplantations. Short-hairpin RNA against glutamate dehydrogenase 2 gene (GLUD2) expression was employed to determine the effects of glutamate and the mutant IDH1 inhibitor AGI-5198 on redox potential in IDH1^R132H-heterozygous cells.RESULTSIn contrast to IDH1^R132H-heterozygous cells, 3D-cultured but not 2D-cultured IDH1^R132H-hemizygous cells were clustered with more malignant gliomas, possessed the glioblastoma mesenchymal signature, and exhibited aggressive tumor growth. Although both extracellular glutamate and AGI-5198 stimulated redox potential for 3D growth of IDH1^R132H-heterozygous cells, GLUD2 expression was required for glutamate, but not AGI-5198, stimulation.CONCLUSION3D culture is more relevant to IDH1^R132H glioma biology. The importance of redox homeostasis in IDH1^R132H glioma suggests that metabolic pathway(s) can be explored for therapeutic targeting, whereas IDH1^R132H inhibitors may have counterproductive consequences in patient treatment.

100 项与 IDH1R132H peptide vaccine(Deutsches Krebsforschungszentrum, Dkfz) 相关的药物交易

登录后查看更多信息