3 years ago

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

Yang Jin, Xiaonan Tao, Xiaofei Liao, Bifeng Liu, Ke Tang, Guanghai Yang, Tingting Liao, Limin Duan, Mei Zhou, Zhilei Lv, Jinshuo Fan, Qi Huang, Shuai Zhang, Shuqing Liu, Yumei Li, Xuan Wang, Pingwei Xu, Juanjuan Xu, Lian Chen, Guorong Hu, Feng Wu, Mengfei Guo

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-. 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.

Publisher URL: http://stm.sciencemag.org/cgi/content/short/11/474/eaat5690

DOI: 10.1126/scitranslmed.aat5690

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