生物素-亲和素系统介导的多模态成像对效应T淋巴细胞靶向胶质瘤的示踪及疗效评估研究

Adoptive immunotherapy has been an important option in glioblastoma therapy, while the specific targeting and treatment assessment are still challenging. Biotin-receptor has been found over-expressing on cell surface of many different tumors, which has been used as target of tumor therapy. Sulfo-N-hydroxysuccinimide (NHS)-biotin can biotinylate cell surface of cytotoxic T lymphocytes (CTLs) quite easily and efficiently, making CTLs targeting cells. Streptavidin (SA) has been used as the vector of different multi-modality imaging probes. In this research, we would use biotin receptor as a new target in glioblastoma immunotherapy, we would label biotinylated CTLs with SA-Alexa750-CLIO, track CTLs and assess treatment with FMT and MR imaging. The aim of this research was to enhance the specific targeting of CTLs to glioblastoma, improve the treatment efficiency assessment by multi-modality imaging and try to illuminate the mechanism. This program is important for making individual treatment plan in the clinic.

细胞免疫治疗已成为胶质瘤治疗的重要方向，治疗细胞的靶向性及疗效评估仍面临诸多挑战。多种肿瘤细胞表面存在生物素受体的过表达并可作为肿瘤靶向治疗的靶点。琥珀酰亚胺基磺酸基生物素可以简单有效的完成效应T淋巴细胞（Cytotoxic T lymphocytes，CTLs）表面生物素化从而完成细胞的靶向。链酶亲和素(Streptavidin，SA)可以作为多模态探针的载体物质并标记生物素化的CTLs。本研究拟以生物素受体作为胶质瘤治疗的新靶点，以SA-Alexa750-CLIO标记生物素化的CTLs，通过FMT成像及MR多序列、多时间点成像示踪CTLs并成像治疗过程中肿瘤微环境的改变从而评估早晚期疗效。本研究的目的是提高CTLs对胶质瘤的特异性识别能力，通过多模态成像使疗效评估更加客观、准确并对相应机制进行研究。该项目对于胶质瘤个体化免疫治疗方案的制定具有重要意义，具有很大的临床应用价值。

细胞毒性T淋巴细胞（CTLs）已成为胶质瘤治疗的重要工具与选择之一，然而其治疗的靶向性及疗效评估仍面临诸多挑战。新的肿瘤治疗靶点不断出现。多种肿瘤细胞表面经证实存在生物素受体的过表达并可作为肿瘤靶向治疗的新靶点。以自身CTLs作为载体替代纳米颗粒载药治疗胶质瘤在载体靶向性、生物相容性及穿越血脑屏障等方便具有很大优势。单宁酸可以同化疗药物硼替佐米（BTZ）的硼基反应而结合，并可同时同细胞表面结合完成细胞载药。本研究以生物素受体作为胶质瘤治疗的新靶点，以生物素、NHS-SPIO及TA-BTZ标记CTLs并载药，通过MR分子成像示踪治疗过程中肿瘤微环境的改变并完成早晚期疗效评估。本研究已经证实生物素受体在胶质瘤细胞表面高表达。CTLs已完成载药、SPIO探针及生物素标记。T细胞复合体经静脉注入体内后，早期疗效（24小时及48小时，T淋巴细胞在肿瘤部位的聚集）已通过MR成像实现，并证实靶向生物素受体的T淋巴细胞复合体对胶质瘤具有很好的靶向性及局部聚集能力，从而证实了以生物素受体为靶点的经生物素修饰的CTLs作为药物载体靶向至胶质瘤部位可行。远期疗效及相关机制验证仍在继续进行。该研究为胶质瘤治疗验证了新的靶点，并有望真正实现CTLs为载体在胶质瘤治疗中实现诊疗一体化。