Using imaging to monitor a fast-growing, luciferase-expressing, intra-adrenal neuroblastoma in a mouse model, van den Bijgaart et al. showed that the HDAC inhibitor Vorinostat alone and with anti-disialoganglioside (GD2) monoclonal antibody, which had minimal impact alone, greatly reduced tumor growth and increased host survival. Immunohistochemistry and flow cytometry showed that Vorinostat alone increased GD2 expression on tumor cells and induced dense accumulations of intratumoral myeloid cells, including MHC IIhiFcRγIhiF4/80hi macrophages and CD11chi DCs. T cell infiltration was unaltered, and NK and B cells were scarce.
Contributed by Paula Hochman
ABSTRACT: Neuroblastoma is a childhood malignancy and in the majority of patients, the primary tumor arises in one of the adrenal glands. Neuroblastoma cells highly express the disialoganglioside GD2, which is the primary target for the development of neuroblastoma immunotherapy. Anti-GD2 mAbs have shown clinical efficacy and are integrated into standard treatment for high-risk neuroblastoma patients. We previously reported synergy between the HDAC inhibitor Vorinostat and anti-GD2 mAbs in a heterotopic, subcutaneous growing neuroblastoma model. Additionally, we have previously developed an orthotopic intra-adrenal neuroblastoma model showing more aggressive tumor growth. Here, we report that anti-GD2 mAb and Vorinostat immunocombination therapy is even more effective in suppressing neuroblastoma growth in the aggressive orthotopic model, resulting in increased animal survival. Intra-adrenal tumors from mice treated with Vorinostat were highly infiltrated with myeloid cells, including macrophages, displaying increased MHCII and Fc-receptor expression. Collectively, these data provide a strong rationale for clinical testing of anti-GD2 mAbs with concomitant Vorinostat in neuroblastoma patients.
Author Info: (1) Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. (2) Holland Proton Therapy Center, Del
Author Info: (1) Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. (2) Holland Proton Therapy Center, Delft, The Netherlands. (3) Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. (4) Central Animal Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands. (5) Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. (6) Bioceros, Utrecht, The Netherlands. (7) Department of Pediatric Oncology, Princess Mxima Center for Pediatric Oncology, Utrecht, The Netherlands. (8) Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
