Autologous tumor cell-derived microparticle-based targeted chemotherapy in lung cancer patients with malignant pleural effusion
Autologous tumor cell-derived microparticle-based targeted chemotherapy in lung cancer patients with malignant pleural effusion
复制标题
自体肿瘤细胞微粒靶向化疗治疗肺癌恶性胸腔积液
DOI：
10.1126/scitranslmed.aat5690
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发表时间：
2019-01-09
影响因子：
17.1
通讯作者：
Jin, Yang
中科院分区：
文献类型：
--
作者：
Guo, Mengfei;Wu, Feng;Jin, Yang
细胞膜衍生的微粒子(MPS)作为细胞间通讯的重要媒介，在天然药物释放系统中的应用越来越受到人们的关注。在这里，我们研究了肿瘤细胞来源的MPS(TMPS)在恶性胸腔积液(MPE)中的治疗潜力。TMPS包装化疗药物甲氨蝶呤(TMPS-MTX)明显抑制了MPE的生长，并对小鼠Lewis肺癌和结肠腺癌细胞诱导的MPE模型提供了生存益处。基于TMPS混合物的潜在益处和最小的毒性，我们进行了一项胸腔内单剂自体TMPS包装甲氨蝶呤(ATMPs-MTX)的人体研究，以评估其安全性、免疫原性和临床活性。我们报告了11例患有MPE的晚期肺癌患者的研究结果。我们发现，制造和输注ATMPs-MTX是可行和安全的，没有证据表明毒性作用为3级或更高。对MPE中肿瘤微环境的评价显示，注射ATMP-MTX后，MPE中的肿瘤细胞和CD163(+)巨噬细胞显著减少，并转化为客观的临床反应。此外，ATMP-MTX还能刺激CD4(+)T细胞释放IL-2，刺激CD8(+)细胞释放干扰素-γ。我们在晚期肺癌MPE中使用ATMPs-MTX的初步经验表明，ATMPs靶向肿瘤细胞和免疫抑制微环境可能是治疗恶性肿瘤的一个有前景的治疗平台。
Cell membrane-derived microparticles (MPs), the critical mediators of intercellular communication, have gained much interest for use as natural drug delivery systems. Here, we examined the therapeutic potential of tumor cell-derived MPs (TMPs) in the context of malignant pleural effusion (MPE). TMPs packaging the chemotherapeutic drug methotrexate (TMPs-MTX) markedly restricted MPE growth and provided a survival benefit in MPE models induced by murine Lewis lung carcinoma and colon adenocarcinoma cells. On the basis of the potential benefit and minimal toxicity of TMPs-MIX, we conducted a human study of intrapleural delivery of a single dose of autologous TMPs packaging methotrexate (ATMPs-MTX) to assess their safety, immunogenicity, and clinical activity. We report our findings on 11 advanced lung cancer patients with MPE. We found that manufacturing and infusing ATMPs-MTX were feasible and safe, without evidence of toxic effects of grade 3 or higher. Evaluation of the tumor microenvironment in MPE demonstrated notable reductions in tumor cells and CD163(+) macrophages in MPE after ATMP-MTX infusion, which then translated into objective clinical responses. Moreover, ATMP-MTX treatment stimulated CD4(+) T cells to release IL-2 and CD8(+) cells to release IFN-gamma. Our initial experience with ATMPs-MTX in advanced lung cancer with MPE suggests that ATMPs targeting malignant cells and the immunosuppressive microenvironment may be a promising therapeutic platform for treating malignancies.