@article{23814dc6a50f4b4ea149c580f1d5b533,
title = "Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment",
abstract = "Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved survival in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, only a minority of NSCLC patients respond to ICIs, highlighting the need for superior immunotherapy. Herein, we report on a nanoparticle-based immunotherapy termed ARAC (Antigen Release Agent and Checkpoint Inhibitor) designed to enhance the efficacy of PD-L1 inhibitor. ARAC is a nanoparticle co-delivering PLK1 inhibitor (volasertib) and PD-L1 antibody. PLK1 is a key mitotic kinase that is overexpressed in various cancers including NSCLC and drives cancer growth. Inhibition of PLK1 selectively kills cancer cells and upregulates PD-L1 expression in surviving cancer cells thereby providing opportunity for ARAC targeted delivery in a feedforward manner. ARAC reduces effective doses of volasertib and PD-L1 antibody by 5-fold in a metastatic lung tumor model (LLC-JSP) and the effect is mainly mediated by CD8+ T cells. ARAC also shows efficacy in another lung tumor model (KLN-205), which does not respond to CTLA-4 and PD-1 inhibitor combination. This study highlights a rational combination strategy to augment existing therapies by utilizing our nanoparticle platform that can load multiple cargo types at once.",
author = "Moataz Reda and Worapol Ngamcherdtrakul and Nelson, {Molly A.} and Natnaree Siriwon and Ruijie Wang and Zaidan, {Husam Y.} and Bejan, {Daniel S.} and Sherif Reda and Hoang, {Ngoc Ha} and Crumrine, {Noah A.} and Rehwaldt, {Justin P.C.} and Akash Bindal and Mills, {Gordon B.} and Gray, {Joe W.} and Wassana Yantasee",
note = "Funding Information: This work was funded by the Wayne D. Kuni & Joan E. Kuni Foundation, National Cancer Institute of the National Institutes of Health (NIH) under Award Number R44CA217534, R44CA265751, and R44CA265752, National Center for Advancing Translational Sciences of the NIH under Award Number R43TR001906, OHSU Knight Cancer Institute{\textquoteright}s Hillcrest Committee Pilot Award, and OHSU Center for Women{\textquoteright}s Health Circle of Giving Award. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. We thank Dr. Sudarshan Anand of OHSU{\textquoteright}s Cell, Developmental and Cancer Biology department for his independent review of the data as required by OHSU{\textquoteright}s conflict of interest guidelines. Thanks to Dr. John Minna and Dr. Rolf Brekken of UT Southwestern Medical Center for their guidance and helpful advice. We acknowledge expert technical assistance by Drs. Stefanie Kaech Petrie and Felice Kelly of the Advanced Light Microscopy Core in the Department of Neurology and Jungers Center at Oregon Health and Science University. We thank Steven Adamou for electron microscopy performed at the Multiscale Microscopy Core, a member of the OHSU University Shared Resource Cores. We thank Dr. Don Gibbon{\textquoteright}s lab at MD Anderson Cancer Center for generous gift of LLC-JSP murine lung cancer cell line. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-31926-9",
language = "English (US)",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}