Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Cultural West Road, Jinan, Shandong Province 250012, China.
NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Shandong University, 44 Cultural West Road, Jinan, Shandong Province 250012, China.
Sci Transl Med. 2022 Aug 3;14(656):eabn1128. doi: 10.1126/scitranslmed.abn1128.
Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating postsurgery residual GSCs is critical for preventing postoperative relapse of this devastating disease, yet effective strategies remain elusive. Here, we report a cavity-injectable nanoporter-hydrogel superstructure that creates GSC-specific chimeric antigen receptor (CAR) macrophages/microglia (MΦs) surrounding the cavity to prevent GBM relapse. Specifically, we demonstrate that the CAR gene-laden nanoporter in the hydrogel can introduce GSC-targeted CAR genes into MΦ nuclei after intracavity delivery to generate CAR-MΦs in mouse models of GBM. These CAR-MΦs were able to seek and engulf GSCs and clear residual GSCs by stimulating an adaptive antitumor immune response in the tumor microenvironment and prevented postoperative glioma relapse by inducing long-term antitumor immunity in mice. In an orthotopic patient-derived glioblastoma humanized mouse model, the combined treatment with nanoporter-hydrogel superstructure and CD47 antibody increased the frequency of positive immune responding cells and suppressed the negative immune regulating cells, conferring a robust tumoricidal immunity surrounding the postsurgical cavity and inhibiting postoperative glioblastoma relapse. Therefore, our work establishes a locoregional treatment strategy for priming cancer stem cell-specific tumoricidal immunity with broad application in patients suffering from recurrent malignancies.
尽管在手术切除后采用了多种模式的治疗方法，但胶质母细胞瘤（GBM）仍然无法治愈。由于手术后残留的胶质瘤干细胞（GSCs），几乎所有 GBM 患者在初始切除病变的狭窄范围内都会复发。跟踪和根除手术后残留的 GSCs 对于防止这种毁灭性疾病的术后复发至关重要，但有效的策略仍然难以捉摸。在这里，我们报告了一种可注射到腔中的纳米载体-水凝胶超结构，该超结构可在腔周围产生 GSC 特异性嵌合抗原受体（CAR）巨噬细胞/小胶质细胞（MΦ），以防止 GBM 复发。具体而言，我们证明了水凝胶中的 CAR 基因负载的纳米载体在腔内递送至后可以将 GSC 靶向的 CAR 基因导入 MΦ 核中，从而在 GBM 小鼠模型中产生 CAR-MΦ。这些 CAR-MΦ 能够通过在肿瘤微环境中刺激适应性抗肿瘤免疫反应来寻找和吞噬 GSCs，并清除残留的 GSCs，从而通过在小鼠中诱导长期抗肿瘤免疫来防止术后神经胶质瘤复发。在原位患者来源的胶质母细胞瘤人源化小鼠模型中，纳米载体-水凝胶超结构与 CD47 抗体的联合治疗增加了阳性免疫反应细胞的频率，并抑制了负性免疫调节细胞，在手术后的腔周围赋予了强大的肿瘤杀伤免疫，并抑制了术后胶质母细胞瘤的复发。因此，我们的工作建立了一种局部治疗策略，用于启动癌症干细胞特异性的肿瘤杀伤免疫，具有广泛的应用前景，适用于患有复发性恶性肿瘤的患者。
