Medical-Industrial Translational Research Center, Fukushima Medical University, Fukushima 960-1295, Japan.
Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima 960-1295, Japan.
Cells. 2019 May 20;8(5):481. doi: 10.3390/cells8050481.
Patient-derived tumor organoids (PDOs) represent a promising preclinical cancer model that better replicates disease, compared with traditional cell culture models. We have established PDOs from various human tumors to accurately and efficiently recapitulate the tissue architecture and function. Molecular targeted therapies with remarkable efficacy are currently in use against various tumors. Thus, there is a need for in vitro functional-potency assays that can be used to test the efficacy of molecular targeted drugs and model complex interactions between immune cells and tumor cells to evaluate the potential for cancer immunotherapy. This study represents an in vitro evaluation of different classes of molecular targeted drugs, including small-molecule inhibitors, monoclonal antibodies, and an antibody-drug conjugate, using lung PDOs. We evaluated epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) inhibitors using a suitable high-throughput assay system. Next, the antibody-dependent cellular cytotoxicity (ADCC) activity of an anti-HER2 monoclonal antibody was evaluated to visualize the interactions of immune cells with PDOs during ADCC responses. Moreover, an evaluation system was developed for the immune checkpoint inhibitors, nivolumab and pembrolizumab, using PDOs. Our results demonstrate that the in vitro assay systems using PDOs were suitable for evaluating molecular targeted drugs under conditions that better reflect pathological conditions.
患者来源的肿瘤类器官（PDO）代表了一种很有前途的临床前癌症模型，与传统的细胞培养模型相比，它能更好地复制疾病。我们已经从各种人类肿瘤中建立了 PDO，以准确有效地再现组织结构和功能。目前，针对各种肿瘤的分子靶向治疗具有显著疗效。因此，需要进行体外功能效力测定，以测试分子靶向药物的疗效，并模拟免疫细胞和肿瘤细胞之间的复杂相互作用，评估癌症免疫治疗的潜力。本研究代表了使用肺 PDO 对不同类别的分子靶向药物（包括小分子抑制剂、单克隆抗体和抗体药物偶联物）的体外评估。我们使用合适的高通量测定系统评估了表皮生长因子受体和人表皮生长因子受体 2（HER2）抑制剂。接下来，评估了抗 HER2 单克隆抗体的抗体依赖性细胞毒性（ADCC）活性，以可视化 ADCC 反应过程中免疫细胞与 PDO 的相互作用。此外，还使用 PDO 开发了免疫检查点抑制剂纳武单抗和帕博利珠单抗的评估系统。我们的结果表明，使用 PDO 的体外测定系统适合在更好地反映病理条件的情况下评估分子靶向药物。
