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

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

Abstract

Introduction: Isocitrate 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).

Methods: AMPLIFY-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.

Perspective: IDH1R132H 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 registration: NCT03893903.

Keywords: Astrocytoma; Avelumab; Brain tumors; Immune checkpoint inhibition; Isocitrate dehydrogenase 1; Oligodendroglioma; Peptide vaccine; Recurrent glioma; T cell receptor sequencing; Window-of-opportunity.

Conflict of interest statement

T.B., M.P. and W.W. are inventors and patent-holders on ‘Peptides for use in treating or diagnosing IDH1R132H positive cancers’ (EP2800580B1). G.T. has served on advisory boards of AbbVie, Bayer, Boehringer Ingelheim, received consulting fees from AbbVie, Bayer; received speaker fees from Medac and Novocure; received travel grants from Novocure, Medac; received research grants from Roche Diagnostics and Medac. M.G. reports honoraria from Roche, Novartis, UCB, Abbvie, Daiichi Sankyo, Novocure, Bayer, Janssen-Cilag, Medac, Merck, Kyowa Kirin, travel support from Novocure and Medac, research grant from Novocure. J.S. has received honoraria for lectures, travel or advisory board participation from Abbvie, Medac, Med-Update, Roche, Novocure and Seagen since 2019. Pfizer and Merck reviewed the manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
AMPLIFY-NEOVAC flow chart. 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 iRANO criteria, treatment will be administered over a period of maximum 43 weeks (primary treatment phase) followed by facultative maintenance treatment
Fig. 2
Fig. 2
Summary of exploratory analyses within AMPLIFY-NEOVAC. T cell and B cell responses will be assessed as primary immunogenicity endpoints. Immunogenicity will be quantitatively and qualitatively correlated with supertype of human leukocyte antigens (HLA) and molecularly-defined IDH1R132H-specific T cells by single cell sequencing technologies. On-trial tumor tissues will be dissociated and TIL will be subjected to single cell sequencing to identify and characterize glioma-reactive T cells and treatment arm (1–3)-specific microenvironmental reprogramming. Liquid biopsies and fecal samples will be subjected to proteomic and transcriptomic analyses, respectively, and correlated to immunogenicity data and clinical endpoints

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