基于纳米尺度天然膜泡结构exosome的双功能抗肿瘤疫苗设计及抗肿瘤效果研究

Anti-tumor therapy that targets the tumor and tumor microenvironment is a promising field in cancer therapy. Tumor vaccines with combined anti-tumor and anti-angiogenesis effects will represent an innovative strategy to develop a highly efficient cancer immunotherapy. The objective of this project is to establish a novel strategy for generating a versatile dendritic cell (DC)-derived exosome (Dex) vaccine with potent efficacy in activating and directing specific T cell responses against both tumor cells and tumor neovasculature for tumor destruction. Exosomes, newly indentified extracellularly secreted nano-sized (30-100 nm) membrane vesicles, can be considered as naturally occurring minimal antigen-presenting units. Dex derived from tumor antigen-pulsed DCs can bear functional MHC/peptide complexes as well as costimulatory molecules for the activation of antigen specific T-cell responses. Dex derived from tumor antigen-pulsed DCs can prime antigen-specific cytotoxic T lymphocytes and repress tumor growth. In addition, Dex loads MHC/peptide complexes from donor cells to recipient cells. Therefore, we intend to use a tumor-homing Dex to transfer MHC/peptide complexes to the tumor and tumor neovasculature for T cell recognition and destruction. Integration of tumor-homing and penetrating properties to Dex by expression of an iRGD (CRGDKGPDC) peptide onto Dex will facilitate the iRGD-Dex to target the αvβ3/5 integrin positive tumor and tumor neovascular endothelial cells. We hypothesize that the iRGD-mediated tumor homing ability of Dex will amplify Dex vaccine efficacy by inducing dual anti-tumor effects against both tumor and tumor neovasculature. Therefore, we hypothesize that iRGD-Dex will boost the host immune system to activate and direct tumor specific T cells responses against tumor and tumor neovasculature. This strategy will have a broad application for many cancer types.

肿瘤微环境调控是抗肿瘤治疗领域中逐渐兴起的治疗策略。针对肿瘤细胞和肿瘤脉管系统的双功能肿瘤疫苗有可能成为协同高效抗肿瘤的免疫治疗方法。Exosome是一类纳米尺度（30-100纳米）的生物膜泡结构，是天然存在的最小的抗原呈递单元，具有抗原负载功能和膜抗原的交换和传递功能。在本项目中，我们设计了一种可同时递呈肿瘤抗原，并具有αvβ3/5整合素靶向性的树突状细胞来源的exosome（Dex）疫苗-iRGD-Dex。我们期望一方面iRGD-Dex疫苗可以刺激宿主免疫，激活识别肿瘤抗原的特异性抗肿瘤免疫反应；另一方面，利用iRGD靶向结构，实现将Dex负载的肿瘤抗原传递给αvβ3/5整合素阳性的肿瘤细胞和新生血管，增强其抗原性，从而促进它们被特异性T细胞的识别和杀伤。我们期望通过双功能iRGD-Dex疫苗的免疫治疗,实现对肿瘤细胞和新生血管双重抑制的高效抗肿瘤新策略。

利用纳米尺度药物和疫苗载体实现肿瘤微环境靶向调控是抗肿瘤治疗领域中逐渐兴起的治疗策略。本项目负责人团队在项目执行期间，探索了exosome等纳米尺度膜泡结构作为肿瘤疫苗载体的应用潜力，初步构建了基于这些膜泡结构的肿瘤疫苗用于抗肿瘤免疫治疗。与此同时，发展了多种基于纳米结构和载体的抗肿瘤药物，用于靶向肿瘤血管等微环境成分，实现基于肿瘤微环境调控的高效低毒治疗以及结合传统疗法的联合治疗。作为研究内容的拓展，项目组进一步探索了纳米载体在跨血脑屏障药物运输方面的潜力。对于以上纳米药物和载体项目组均进行了初步的理化性质表征、体内过程和生物安全性评价，并验证其在动物模型中具有良好的治疗效果。本项目在国际知名期刊上发表论文5篇，部分研究成果得到Nature Biomedical Engineering等重要期刊的报道。