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Oncoimmunology. 2016 Mar 28;5(6):e1164919. doi: 10.1080/2162402X.2016.1164919. eCollection 2016 Jun.

Anti-GD2 mAb and Vorinostat synergize in the treatment of neuroblastoma.

Author information

1
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.
2
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, The Netherlands.
3
EPIRUS Biopharmaceuticals Netherlands B.V. , Utrecht, The Netherlands.
4
Department of Pediatric Oncology, Radboud University Medical Center, Nijmegen, The Netherlands; Princes Máxima Center for Pediatric Oncology, De Bilt, The Netherlands.

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.

KEYWORDS:

Anti-gd2 mAb therapy; histone deacytelase inhibitor; immunotherapy; myeloid-derived suppressor cell; neuroblastoma

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