Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, Massachusetts, USA.
Department of Surgery, Division of Pediatric Surgery, University of Illinois at Chicago, Chicago, Illinois, USA.
J Biomed Mater Res A. 2021 Aug;109(8):1393-1405. doi: 10.1002/jbm.a.37131. Epub 2020 Dec 10.
Neuroblastoma is the most common extracranial solid tumor of childhood and is associated with poor survival in high risk patients. Recently, dinutuximab (DNX) has emerged as an effective immunotherapy to treat patients with high risk neuroblastoma. DNX works through the induction of cell lysis via complement-dependent cytotoxicity (CDC) or antibody dependent cellular cytotoxicity (ADCC). However, one third of patients who undergo DNX treatment exhibit tumor relapse and the therapy is dose limited by side effects such as severe pain. To overcome delivery challenges of DNX, including large size and dose limiting side effects, we fabricated a delivery system capable of sustained local delivery of bioactive DNX utilizing silk fibroin. We evaluated the impact of silk properties (MW, crystallinity, and concentration) on release properties and confirmed the bioactivity of the release product. Additionally, we observed that the effectiveness of CDC induction by DNX could be correlated to the GD2 expression level of the target cells, with both the intravenous DNX formulation and the released DNX. Collectively, these data highlights a strategy to overcome delivery challenges and potentially improve therapeutic efficacy in cells expressing heterogenous levels of GD2.
神经母细胞瘤是儿童最常见的颅外实体瘤，与高危患者的生存率差有关。最近，dinutuximab（DNX）已成为治疗高危神经母细胞瘤患者的有效免疫疗法。DNX 通过补体依赖性细胞毒性（CDC）或抗体依赖性细胞毒性（ADCC）诱导细胞裂解而起作用。然而，三分之一接受 DNX 治疗的患者出现肿瘤复发，并且该疗法因严重疼痛等副作用而受到剂量限制。为了克服 DNX 的递药挑战，包括其较大的尺寸和剂量限制的副作用，我们使用丝素蛋白构建了一个能够持续局部递送生物活性 DNX 的递药系统。我们评估了丝素性质（MW、结晶度和浓度）对释放性质的影响，并证实了释放产物的生物活性。此外，我们观察到 DNX 诱导 CDC 的效果可以与靶细胞的 GD2 表达水平相关，无论是静脉内 DNX 制剂还是释放的 DNX。总之，这些数据强调了一种克服递药挑战并可能提高表达异质 GD2 水平的细胞治疗效果的策略。
