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Myeloid Cell-Targeted Nanocarriers Efficiently Inhibit Cellular Inhibitor of Apoptosis for Cancer Immunotherapy
Journal article   Open access   Peer reviewed

Myeloid Cell-Targeted Nanocarriers Efficiently Inhibit Cellular Inhibitor of Apoptosis for Cancer Immunotherapy

Peter D. Koch, Christopher B. Rodell, Rainer H. Kohler, Mikael J. Pittet and Ralph Weissleder
Cell chemical biology, v 27(1), pp 94-104
16 Jan 2020
PMID: 31902676
url
https://doi.org/10.1016/j.chembiol.2019.12.007View
Published, Version of Record (VoR)Open Access (Publisher-Specific) Open

Abstract

cancer dendritic cells drug delivery high-content drug screening immunotherapy interleukin-12 nanoparticle
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. [Display omitted] •LCL161 activates IL-12 production in murine dendritic cells•LCL161 can be complexed to nanoparticles for delivery to the tumor microenvironment•LCL161 nanoparticles regress tumors and outperform a free drug control Koch et al. describe the development of LCL161 nanoparticles for cancer immunotherapy. These nanoparticles deliver the small-molecule drug LCL161 to intratumoral dendritic cells, where it stimulates production of IL-12. This therapeutic could greatly enhance the efficacy of current checkpoint inhibitors.

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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
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