肿瘤细胞治疗研究
英文原题：Sustained Endocytosis Inhibition via Locally-Injected Drug-Eluting Hydrogel Improves ADCC-Mediated Antibody Therapy in Colorectal Cancer.
在人源化患者来源异种移植模型中，单次注射Gel@Cmab/PCZ，剂量为常规西妥昔单抗的三分之一，实现了91%的肿瘤生长抑制，促进了NK细胞向肿瘤组织的浸润及其抗体依赖性细胞介导的细胞毒性作用。
表皮生长因子受体（EGFR）是RAS/RAF野生型结直肠癌（CRC）已验证的治疗靶点。然而，西妥昔单抗等基于单克隆抗体的抗EGFR疗法效果有限。本研究基于接受西妥昔单抗治疗患者的回顾性分析，发现EGFR内化与CRC患者治疗应答不佳及预后较差相关。我们进一步证明，内吞作用抑制剂丙氯拉嗪（PCZ）可将隐藏于细胞内的EGFR转移至细胞表面，提高治疗性抗体结合。因此，我们构建了一种共载西妥昔单抗和PCZ的温敏水凝胶（Gel@Cmab/PCZ），以持续抑制内吞作用并有效递送西妥昔单抗。瘤周注射Gel@Cmab/PCZ在皮下和原位CRC肿瘤模型中显示强效抗肿瘤作用；与化疗联合时，可完全消除肝转移。在人源化患者来源异种移植模型中，单次注射仅含常规西妥昔单抗剂量三分之一的Gel@Cmab/PCZ，即可抑制91%的肿瘤生长，并促进NK细胞浸润肿瘤组织及其抗体依赖性细胞介导细胞毒作用。本研究提出一种新策略，可增强单克隆抗体介导的CRC抗肿瘤应答。
The epidermal growth factor receptor (EGFR) is a validated therapeutic target for RAS/RAF wild-type colorectal cancer (CRC). However, monoclonal antibody-based anti-EGFR therapies such as cetuximab have limited effectiveness. Herein, it is identified that EGFR internalization is associated with poor treatment response and prognosis in patients with CRC, based on a retrospective analysis of patients treated with cetuximab. It is further demonstrated that the endocytosis inhibitor prochlorperazine (PCZ) can move EGFR, which is hidden inside the cell, to the cell surface to improve therapeutic antibody binding. Thus, a thermosensitive hydrogel co-loaded with cetuximab and PCZ (Gel@Cmab/PCZ) is constructed for sustained inhibition of endocytosis and effective cetuximab delivery. Peritumoral injection of Gel@Cmab/PCZ shows strong antitumor efficacy in subcutaneous and orthotopic CRC tumor models and completely abrogated liver metastasis when combined with chemotherapy. In a humanized patient-derived xenograft model, a single injection of Gel@Cmab/PCZ with one-third of the conventional cetuximab dose achieved 91% tumor growth inhibition, which promoted NK cell infiltration into tumor tissues and their antibody-dependent cell-mediated cytotoxicity effect. This study represents a novel strategy to boost the monoclonal antibody-mediated anti-tumor response in CRC.
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