van den Bijgaart Renske J E, Kroesen Michiel, Brok Ingrid C, Reijnen Daphne, Wassink Melissa, Boon Louis, Hoogerbrugge Peter M, Adema Gosse J
Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
Holland Proton Therapy Center, Delft, The Netherlands.
Oncoimmunology. 2020 Sep 20;9(1):1817653. doi: 10.1080/2162402X.2020.1817653.
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.
神经母细胞瘤是一种儿童恶性肿瘤，在大多数患者中，原发肿瘤起源于肾上腺之一。神经母细胞瘤细胞高度表达双唾液酸神经节苷脂GD2，这是神经母细胞瘤免疫治疗发展的主要靶点。抗GD2单克隆抗体已显示出临床疗效，并被纳入高危神经母细胞瘤患者的标准治疗中。我们之前报道了组蛋白去乙酰化酶抑制剂伏立诺他与抗GD2单克隆抗体在异位皮下生长的神经母细胞瘤模型中的协同作用。此外，我们之前还建立了一种肾上腺原位神经母细胞瘤模型，该模型显示肿瘤生长更具侵袭性。在此，我们报告抗GD2单克隆抗体与伏立诺他免疫联合疗法在侵袭性原位模型中抑制神经母细胞瘤生长方面甚至更有效，从而提高了动物存活率。用伏立诺他治疗的小鼠的肾上腺内肿瘤被包括巨噬细胞在内的髓样细胞高度浸润，显示出MHCII和Fc受体表达增加。总的来说，这些数据为在神经母细胞瘤患者中同时使用抗GD2单克隆抗体和伏立诺他进行临床试验提供了有力的理论依据。
