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

Michiel Kroesen, Christian Büll, Paul R. Gielen, Ingrid C. Brok, Inna Armandari, Melissa Wassink, Maaike W.G. Looman, Louis Boon, Martijn H. den Brok, Peter M. Hoogerbrugge, Gosse J. Adema

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

47 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Artikelnummere1164919
TijdschriftOncoImmunology
Volume5
Nummer van het tijdschrift6
DOI's
StatusGepubliceerd - 2 jun. 2016

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