基于 IGF1R decoy 介导的小胶质细胞移植治疗胶质瘤的新策略探究

胶质母细胞瘤（GBM）是中枢神经系统常见恶性肿瘤，至今仍缺乏有效治疗手段。基于小分子抑制剂和细胞治疗等方法为GBM靶向治疗提供了新方向。然而由于血脑屏障和免疫抑制环境的存在，如何实现小分子或免疫细胞脑内高效递送并杀死肿瘤细胞仍是亟待解决的关键问题。作为大脑中特化的免疫细胞，小胶质细胞可以通过外源移植方式进行替换并长期存活。因此，基于小胶质细胞作为治疗载体的策略将很可能成为GBM治疗的新方向。申请人前期的工作明确了IGF1R作为GBM高效且特异的分子靶点。本研究将探索利用巨噬细胞/小胶质细胞作为细胞载体，通过骨髓/脑内原位移植方式，用高表达IGF1诱饵受体（IGF1R decoy）的巨噬细胞/小胶质细胞替换自发或原位移植胶质瘤模型中的内源性小胶质细胞，从而通过有效阻断微环境中IGF1信号通路实现对胶质瘤靶向治疗。本项目将为胶质瘤靶向治疗及脑内药物高效递送提供新思路，具有较强的临床转化潜能。

Glioblastoma (GBM) is a common and malignant tumor of the central nervous system and lack effective treatment. Small molecule inhibitors and cell therapy provide new directions for GBM targeted therapy. However, due to the blood-brain barrier and the immunosuppressive environment in the brain, how to deliver small molecular inhibitors or immune cells efficiently is still the fundamental question in the field. As the specialized immune cells in the brain, microglia can be functionally replaced by exogenous macrophage/microglia through transplantation. Therefore, microglia functioning as the treatment vehicle can be a new direction of GBM treatment. The applicant’s previous work has proved that Insulin-like Growth Factor 1 Receptor (IGF1R) is an effective and specific treatment target of glioblastoma. In this study, we will use macrophages/microglia expressing IGF1R decoy to replace the endogenous microglia, through bone marrow transplantation or orthotopic transplantation, in spontaneous or orthotopic transplantation glioma model. Thus, treating glioma by effectively blocking the IGF1 signaling pathway in the microenvironment. This project will provide new insight for targeted therapy of glioma and efficient drug delivering to the brain, and it has strong potential of clinical transformation.