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

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

doi:10.1080/2162402x.2016.1164919

Abstract

ABSTRACTNeuroblastoma (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.

Highlights

NBL is a childhood malignancy of the sympathetic nervous system accounting for 12% of cancer-associated deaths in children under 15 y of age.[1]
We report that anti-GD2 monoclonal antibody (mAb) therapy combined with the histone deacetylase inhibitors (HDACi) Vorinostat results in synergistic antitumor effects in this novel NBL mouse model
To determine whether the murine TH-MYCN cell lines 9464D and 975A2 were sensitive to HDACi-mediated cell death, these cells were exposed to increasing concentrations of various HDACi, after which viability was determined via standard MTT metabolic activity assays

Summary

Introduction

NBL is a childhood malignancy of the sympathetic nervous system accounting for 12% of cancer-associated deaths in children under 15 y of age.[1] Patients with high-risk NBL, including MYCN-amplified NBL, have a poor long-term survival despite intensive multimodal treatment.[2] In a recent phase III clinical trial, immunotherapy improved the event-free survival of highrisk NBL patients by around 20%.3. The immunotherapy in this trial consisted of a tumor-specific mAb directed toward the tumor antigen GD2 in combination with administration of immune stimulating cytokines IL-2 and GM-CSF. Further improvement of NBL treatment is needed to increase the survival of these pediatric patients

Methods

Results

Conclusion