title: Anti-GD2 mAb and Vorinostat synergize in the treatment of neuroblastoma.
abstract: Neuroblastoma (NBL) is a childhood malignancy of the sympathetic nervous system. For high-risk NBL patients, the mortality rate is still over 50%, despite intensive multimodal treatment. Anti-GD2 monoclonal antibody (mAB) in combination with systemic cytokine immunotherapy has shown clinical efficacy in high-risk NBL patients. Targeted therapy using histone deacetylase inhibitors (HDACi) is currently being explored in cancer treatment and already shows promising results. Using our recently developed transplantable TH-MYCN NBL model, we here report that the HDAC inhibitor Vorinostat synergizes with anti-GD2 mAb therapy in reducing NBL tumor growth. Further mechanistic studies uncovered multiple mechanisms for the observed synergy, including Vorinostat-induced specific NBL cell death and upregulation of the tumor antigen GD2 on the cell surface of surviving NBL cells. Moreover, Vorinostat created a permissive tumor microenvironment (TME) for tumor-directed mAb therapy by increasing macrophage effector cells expressing high levels of Fc-receptors (FcR) and decreasing the number and function of myeloid-derived suppressor cells (MDSC). Collectively, these data imply further testing of other epigenetic modulators with immunotherapy and provide a strong basis for clinical testing of anti-GD2 plus Vorinostat combination therapy in NBL patients.
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Pediatric Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Kroesen
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Büll
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gielen
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Brok
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
authors.forename: Inna
authors.initials: I
authors.lastname: Armandari
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
authors.forename: Melissa
authors.initials: M
authors.lastname: Wassink
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
authors.forename: Maaike W G
authors.initials: MW
authors.lastname: Looman
authors.affiliation: EPIRUS Biopharmaceuticals Netherlands B.V. , Utrecht, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
authors.forename: Martijn H
authors.initials: MH
authors.lastname: den Brok
authors.affiliation: Department of Pediatric Oncology, Radboud University Medical Center, Nijmegen, The Netherlands; Princes Máxima Center for Pediatric Oncology, De Bilt, The Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
keywords: Anti-gd2 mAb therapy; histone deacytelase inhibitor; immunotherapy; myeloid-derived suppressor cell; neuroblastoma