重塑肿瘤微血管增效EGFRvⅢ-CAR T靶向治疗胶质母细胞瘤的多模态MRI研究

Abnormal tumor vasculature not only hinders the infiltration of chimeric antigen receptors T (CAR-T) cells into the tumor parenchyma, but also suppresses the CAR-T function in tumors. Thus, tumor microvascular remodeling based on anti-angiogenesis may enhance CAR-T immunotherapy to solid tumors. However, lacking the effective non-invasive tracking methods for monitoring tumor microvascular remodeling window to determine the right time to transplant CAR-T cells, which laid difficulties to apply and develop this new CAR-T therapeutic strategy. Based on our previous studies that EGFRvⅢ-targeted CAR-T cells could successfully migrate to and mediate regression in tumor of NOD-SCID mice orthotopic glioblastoma model, we plan to target tumor vasculature with lower dose of antiangiogenic agents. To obtain the imaging biomarkers for evaluating tumor microvascular remodeling by analyzing the correlation and consistency of MRI and pathology related parameters, which could guide to determine the right time to transplant CAR-T cells. And we used the ultrasmall superparamagnetic iron oxide labeled cell tracking technique with 7.0 T MRI to evaluate the penetration and persistence of CAR-T cells in tumor. By doing this, we will establish a new technological platform and evaluation system for in vivo tracking of tumor microvascular remodeling enhancing EGFRvⅢ-CAR T immunotherapy to glioblastoma, which will have great significance to the development of CAR-T immunotherapy and improvement of therapeutic efficacy in solid tumors.

结构功能异常的肿瘤微血管是阻碍CAR-T细胞进入实体瘤深部并发挥治疗效果的重要因素。基于抗血管策略重塑肿瘤微血管可能成为增效CAR-T靶向治疗实体瘤的有效手段。遗憾的是，目前缺乏对肿瘤微血管重塑时间窗的活体示踪手段用以确定抗血管干预后CAR-T细胞的回输时机，这将严重阻碍这一新型策略在治疗实体瘤方面的应用和发展。本项目基于前期以EGFRvⅢ为靶抗原的CAR-T细胞治疗免疫缺陷鼠胶质母细胞瘤原位种植模型的成功测试，采用低剂量抗血管药物重塑肿瘤微血管，通过连续动态解析影像-病理参数的关联性和一致性，获得活体评估肿瘤微血管结构和功能重塑的影像学标记，指导选择CAR-T细胞的回输时机，并运用纳米铁颗粒直接标记MRI成像技术示踪CAR-T细胞在瘤内的动态变化，建立重塑肿瘤微血管增效CAR-T靶向治疗胶质母细胞瘤的无创性活体示踪技术平台和评价体系，推动CAR-T治疗技术在实体瘤成功开展和效果提高。

结构功能异常的肿瘤微血管是阻碍CAR-T细胞进入实体瘤深部并发挥治疗效果的重要因素。基于抗血管策略重塑肿瘤微血管可能成为增效CAR-T靶向治疗实体瘤的有效手段。遗憾的是，目前缺乏对肿瘤微血管重塑时间窗的活体示踪手段用以确定抗血管干预后CAR-T细胞的回输时机，这将严重阻碍这一新型策略在治疗实体瘤方面的应用和发展。在本项目的资助下，我们围绕如何准确判定肿瘤微血管重塑的时间窗以获得联合CAR-T治疗的最佳时机、如何及时评估重塑肿瘤微血管能否增效CAR-T靶向治疗肿瘤以对治疗方案做出合理调整这两个关键问题，使用免疫缺陷鼠胶质母细胞瘤原位种植模型，采用低剂量抗血管药物重塑肿瘤微血管，通过连续动态解析影像-病理参数的关联性和一致性，获得活体评估肿瘤微血管结构和功能重塑的影像学标记物（IVIM参数D*和DCE-MRI参数Ktrans），初步探讨肿瘤微血管重塑的分子机制。并运用纳米铁颗粒标记CAR-T细胞，MRI成像技术示踪CAR-T细胞在瘤内的动态变化，建立了重塑肿瘤微血管增效CAR-T靶向治疗胶质母细胞瘤的无创性活体示踪技术平台和评价体系。总之，我们通过重塑肿瘤微血管调控CAR-T细胞对胶质母细胞瘤靶向、穿透、瘤内积聚及治疗效果的MRI多模态成像示踪研究，获得肿瘤微血管重塑的MRI影像学标记，建立基于抗血管策略重塑肿瘤微血管增效CAR-T靶向胶质母细胞瘤的无创性活体示踪平台及评价体系。用于指导基于抗血管重塑肿瘤微血管增效CAR-T靶向GBM的方案制定和改进，改善目前GBM等实体瘤CAR-T治疗的困境，推动CAR-T治疗技术在实体瘤成功开展和效果提高。. 项目的各项研究工作按照申请书的计划进行，在各个阶段都取得了较好的进展和成果，培养了数名科技青年骨干，达到了预期目标。目前，在本项目的资助下，项目组成员已发表SCI论著6篇，并有其它研究成果正在陆续整理发表中。.