Autologous tumor cell-derived microparticle-based targeted chemotherapy in lung cancer patients with malignant pleural effusion

• Published in: Science translational medicine 2019-01, Vol.11 (474)
• Main Authors: Guo, Mengfei, Wu, Feng, Hu, Guorong, Chen, Lian, Xu, Juanjuan, Xu, Pingwei, Wang, Xuan, Li, Yumei, Liu, Shuqing, Zhang, Shuai, Huang, Qi, Fan, Jinshuo, Lv, Zhilei, Zhou, Mei, Duan, Limin, Liao, Tingting, Yang, Guanghai, Tang, Ke, Liu, Bifeng, Liao, Xiaofei, Tao, Xiaonan, Jin, Yang
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animal models; Animals; CD163 antigen; CD4 antigen; CD8 antigen; Cell Death - drug effects; Cell interactions; Cell Line, Tumor; Cell membranes; Cell signaling; Cell-Derived Microparticles - metabolism; Cell-Derived Microparticles - ultrastructure; Chemotherapy; Colon; Disease Models, Animal; Drug delivery; Endocytosis; Humans; Immunogenicity; Interleukin 2; Lung cancer; Lung carcinoma; Lung Neoplasms - complications; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lymphocytes T; Macrophages; Methotrexate; Methotrexate - pharmacology; Methotrexate - therapeutic use; Mice, Inbred C57BL; Microparticles; Neoplasm Staging; Patients; Pleural effusion; Pleural Effusion, Malignant - complications; Pleural Effusion, Malignant - immunology; Pleural Effusion, Malignant - pathology; Tissue Distribution - drug effects; Toxicity; Transplantation, Autologous; Tumor cells; Tumor Microenvironment - drug effects; γ-Interferon
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aat5690

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-MTX, 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-γ. 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.