Myeloid Cell-Targeted Nanocarriers Efficiently Inhibit Cellular Inhibitor of Apoptosis for Cancer Immunotherapy.,Cell Chemical Biology

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Myeloid Cell-Targeted Nanocarriers Efficiently Inhibit Cellular Inhibitor of Apoptosis for Cancer Immunotherapy.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2020-01-02 , DOI: 10.1016/j.chembiol.2019.12.007
Peter D Koch ₁ , Christopher B Rodell ₁ , Rainer H Kohler ₁ , Mikael J Pittet ₁ , Ralph Weissleder ₂

Affiliation

Immune-checkpoint blockers can promote sustained clinical responses in a subset of cancer patients. Recent research has shown that a subpopulation of tumor-infiltrating dendritic cells functions as gatekeepers, sensitizing tumors to anti-PD-1 treatment via production of interleukin-12 (IL-12). Hypothesizing that myeloid cell-targeted nanomaterials could be used to deliver small-molecule IL-12 inducers, we performed high-content image-based screening to identify the most efficacious small-molecule compounds. Using one lead candidate, LCL161, we created a myeloid-targeted nanoformulation that induced IL-12 production in intratumoral myeloid cells in vivo, slowed tumor growth as a monotherapy, and had no significant systemic toxicity. These results pave the way for developing combination immunotherapeutics by harnessing IL-12 production for immunostimulation.

中文翻译：

靶向髓样细胞的纳米载体可有效抑制细胞凋亡的细胞抑制剂，用于癌症免疫治疗。

免疫检查点阻滞剂可以促进一部分癌症患者的持续临床反应。最近的研究表明，肿瘤浸润树突状细胞亚群起着看门人的作用，通过产生白介素12（IL-12）使肿瘤对抗PD-1治疗敏感。推测髓样细胞靶向的纳米材料可用于递送小分子IL-12诱导剂，我们进行了基于图像的高含量筛选，以鉴定最有效的小分子化合物。使用一种潜在的候选药物LCL161，我们创建了一种靶向髓样的纳米制剂，该纳米制剂可在体内诱导肿瘤内髓样细胞中IL-12的产生，作为一种单一疗法可减缓肿瘤的生长，并且没有明显的全身毒性。

更新日期：2020-01-04

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