自体肿瘤细胞来源的微颗粒包裹甲氨蝶呤靶向治疗恶性胸腔积液的机制研究

Malignant pleural effusion(MPE) as a common complication of advanced lung cancer is lack of efficient treatments. We have successfully produced tumor cell-derived microparticles packaging chemotherapy drugs and confirmed that this new integrative targeted biochemotherapy treatment could effectively restrain tumor growth at cellular and animal levels. And we designed and registered a clinical trail about autologous tumor cell derived microparticles packaging methotrexate for the treatment of MPE firstly and get approved by the International Clinical Trials Registry Platform. This new method could control tumor growth in vivo effectively and induced pleural adhesion in our early clinical study. So we attempt to explore the anticancer effect and related immune regulation mechanism of MTX-ATMPs in MPE treatment. We will investigate the phenotype and function changes of tumor killer cells(CD8+T cell、NK）and immunosuppressive cells（Treg、TAM and MDSC）in the samples from clinical patients and mices with MPE to explain the exact regulation mechanism. Our programe aims to clarify the anticancer effect and the invloed immunological mechanism of MTX-ATMPs and establish the theoretical foundation for the clinical translation of this new anti-tumor biochemotherapy.

恶性胸腔积液（MPE）是晚期肺癌病人常见并发症，目前临床上缺乏有效治疗手段。课题组成功制备了包裹化疗药物的肿瘤细胞来源的微颗粒，在细胞和动物水平证实了该新型一体化生物化疗方法可有效抗肿瘤并具有靶向性；申请人设计了自体肿瘤细胞来源的微颗粒包裹甲氨蝶呤（MTX-ATMPs）治疗MPE的临床研究，并首次成功注册国际临床试验，前期研究发现其具有较明显的抗肿瘤及胸膜粘连效应。基于此，我们拟探讨MTX-ATMPs治疗MPE中的抗肿瘤效应及相关机制：利用临床标本并结合MPE小鼠模型，研究其疗效及治疗前后抗肿瘤免疫细胞（CD8+T细胞、NK细胞）及免疫抑制细胞（Treg、TAM及MDSC）的分布、表型功能和相关炎性因子改变，阐明其抗肿瘤和胸膜粘连效应及免疫调控机制。本课题旨在通过ATMPs包裹化疗药物治疗肿瘤的作用和机制研究，为这种首创的新型肿瘤生物化疗技术的临床深入转化提供理论依据。

微颗粒是体内各种细胞在应激时分泌至胞外的包裹胞浆内容物的囊泡样亚细胞结构体，TMPs-MTX是基于肿瘤细胞来源微颗粒的靶向化疗平台。本项目主要研究微颗粒作为新型自体来源的生物载体包裹化疗药物甲氨蝶呤治疗肺癌合并恶性胸腔积液的作用及相关免疫学机制。目前研究中，我们使用TMPs这种新型的药物载体去转运化疗药物甲氨蝶呤，并在免疫活性的腺癌小鼠MPE模型及肺癌合并MPE患者中研究其靶向毒性效应及相应的免疫调节机制。研究结果表明: 体外TMPs-MTX可有效杀伤多种肿瘤细胞及巨噬细胞。ATMPs-MTX在C57BL/6小鼠MPE模型中及肺腺癌合并MPE患者中均有良好疗效。我们这项小型临床实验初步表明ATMPs-MTX经胸腔内给药用于治疗肺腺癌合并MPE患者是安全、无毒和可耐受的。此外，动物和临床实验均表明ATMPs-MTX的作用不仅局限于对肿瘤细胞的杀伤，还可能表现为巨噬细胞的耗竭和淋巴细胞活化的增加。本研究通过将自体肿瘤细胞释放的微颗粒应用作为新一代的生物相容性的药物载体，为晚期肺癌合并恶性胸腔积液的治疗提供了一个新型的个性化策略治疗。