DEC205-ATMPs靶向疫苗联合ATMPs-MTX生物化疗治疗恶性胸腔积液的作用及机制研究

Malignant Pleural Effusion(MPE) is an important complication for patients with progressive lung cancer and difficult to treat and manage. We have successfully registered a international clinical trail “ autologous tumor cell derived microparticles packaging methotrexate(ATMPs-MTX) for the treatment of MPE” based on the targeting ability and cytotoxicity of ATMPs-MTX and the immunostimulatory ATMPs.Preliminary applications show this new integrative targeted biochemotherapy treatment could effectively control MPE, prolong survival and improve the pleural cavity miroenvironment,though the long-term antitumor immune response is relatively weak. Thus, we have developed the DEC205-ATMPs vaccine to activate antitumor immune response through targeted delivery of immunogenic ATMPs to dendritic cells. . Therefore, we aim to study the synergistical therapic effect of DEC205-ATMPs and ATMPs-MTX in MPE and the underlying mechanism. First, we will prepare DEC205-ATMPs vaccine, and assess the action of targeted antigen-presenting to DC and antitumor immune stimulatory role of DEC205-ATMPs. Second, we will assess synergistical therapic role of intrathoracic injection of ATMPs-MTX and subcutaneous vaccination of DEC205-ATMPs in mice MPE model. Third, we will investage the effect of this synergistic therapy on local pleural cavity and systemic immunity and the underlying mechanism. This study is a pioneering and expanding research for ATMPs-mediated personalized and integrative biological target therapy and is of great significance for translational medicine.

恶性胸腔积液（MPE）难以控制，是肺癌晚期进展的严重表现。我们前期首创利用自体肿瘤细胞来源微颗粒包裹甲氨蝶呤（ATMPs-MTX）的靶向肿瘤杀伤作用及免疫刺激效应，首创开展了“ATMPs-MTX治疗MPE”的国际注册临床研究；结果初步显示该靶向生物化疗能明显控制MPE、改善免疫微环境、延长生存时间，但发挥长期抗肿瘤免疫效应有限。为此我们制备了DEC205-ATMPs疫苗以期通过靶向传递免疫原性ATMPs至DC激活全身抗肿瘤免疫。.在上述基础上，我们就DEC205-ATMPs靶向疫苗联合ATMPs-MTX生物化疗治疗MPE进行研究：⑴制备、鉴定疫苗，明确其靶向DC抗原呈递及抗肿瘤免疫刺激作用；⑵小鼠MPE模型验证联合治疗效果；⑶对小鼠MPE胸腔及全身抗肿瘤免疫的作用和机制。本课题为ATMPs介导的肿瘤个体化、靶向疫苗联合生物化疗创新治疗技术的开拓性延伸，具有重要转化医学意义。

肿瘤细胞微颗粒携带了肿瘤细胞大量生物信息学特征，是良好的肿瘤抗原载体。本项目主要利用免疫佐剂修饰肿瘤微颗粒合成新型抗肿瘤疫苗治疗肺癌并探讨其相关免疫学机制。在这项研究中，我们主要研究这种新型的抗肿瘤疫苗对于抗原提呈细胞(树突状细胞和巨噬细胞)的激活能力以及杀伤T细胞激活的能力，并在免疫活性的肺腺癌小鼠模型中研究其抗肿瘤能力及相应的免疫调节机制。研究结果表明: 新型的抗肿瘤疫苗可促进抗原提呈细胞的激活，从而上调了T细胞杀伤肿瘤的能力。在C57BL/6小鼠肺腺癌皮下瘤模型中有良好的抑瘤效应。此外，也证明了新型抗肿瘤疫苗的安全性。本研究利用肿瘤细胞释放的微颗粒合成新型的抗肿瘤疫苗，为肺癌的治疗提供了一个新型的个性化策略治疗。