Myeloid Cell-Targeted Nanocarriers Efficiently Inhibit Cellular Inhibitor of Apoptosis for Cancer Immunotherapy. Issue 1 (16th January 2020)

• Record Type: Journal Article
• Authors: Koch, Peter D.; Rodell, Christopher B.; Kohler, Rainer H.; Pittet, Mikael J.; Weissleder, Ralph
• Is Part Of: Cell chemical biology. Volume 27:Issue 1(2020)
• Page Start: 94
• Page End: 104.e5
• Publication Date: 2020-01-16
• Subjects: cancer -- immunotherapy -- high-content drug screening -- dendritic cells -- interleukin-12 -- nanoparticle -- drug delivery; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2019.12.007
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: 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 Abstract : 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.