磁纳米疫苗联合CTLA-4抑制剂对胶质瘤免疫治疗的研究

Immunotherapy has attracted much attention recently due to the high specificity, mild side effects and long-term memory. The lack of effective antigen presenting and localized immunosuppressive microenvironment often lead to the failure of immunotherapy. We try to establish new magnetic nanovaccines functionalized with EphA2 protein, which is overexpressed in glioma. After co-incubated with these magnetic nanovaccines, DCs could be activated and will be injected into the rats with orthotopic glioma via the tail vein. Simultaneously，anti-CTLA-4 therapy will be combined and 9.4T MRI will be used to track DCs, measure the growth of tumors and the survive time to evaluate the therapy effects and explore the immunotherapy mechanism. we expect the combination of magnetic nanovaccines and anti-CTLA-4 could effectively activate the immune system, inhibit the immune inhibitory activity of Treg cells, and enhance the CTL-mediated specific tumor immune response while activating immune memory effect. The growth, metastasis and recurrence of gliomas would be effectively inhibited and the survival of tumor-bearing rats would be prolonged. It is expected this new magnetic nanovaccines would provide a new chance for glioma therapy.

脑胶质瘤免疫治疗特异性强、副作用轻、可长期记忆，成为近年来治疗的新热点。因缺乏有效抗原递呈及肿瘤局部存在免疫抑制微环境常导致免疫治疗失败。本项目拟将胶质瘤高表达的EphA2蛋白作为抗原构建针对胶质瘤的新型磁纳米疫苗，体外刺激树突状细胞（DCs）成熟后经静脉回输原位胶质瘤荷瘤鼠体内，联合应用CTLA-4免疫检查点抑制剂，利用9.4T MRI示踪DCs、观察肿瘤生长及大鼠生存时间，评估治疗疗效，探索肿瘤免疫反应机制。预期该磁纳米疫苗联合抗CTLA-4治疗可有效激活机体免疫系统，阻断调节T细胞的免疫抑制活性，增强CTL介导的特异性肿瘤免疫反应，同时激活免疫记忆效应，有效抑制胶质瘤生长、转移及复发，延长荷瘤鼠生存期，为胶质瘤治疗提供新的契机。

因缺乏有效抗原递呈及肿瘤局部存在免疫抑制微环境常导致胶质瘤免疫治疗的失败。本项目将胶质瘤高表达的EphA2蛋白作为抗原构建针对胶质瘤的新型磁纳米疫苗，体外与DCs共孵育后回输荷瘤鼠体内，联合应用CTLA-4免疫检查点抑制剂，利用MRI监测、评估治疗疗效，同时通过特异性抗体抑制巨噬细胞M1型向M2型转换，解除胶质瘤免疫抑制微环境，提高荷瘤小鼠存活率，为胶质瘤免疫治疗提供了新的治疗思路，并对其相关免疫机制进行了初步探索。