| Autor: |
Moataz Reda, Worapol Ngamcherdtrakul, Molly Nelson, Natnaree Siriwon, Ruijie Wang, Husam Zaidan, Daniel Bejan, Sherif Reda, Ngoc Hoang, Noah Crumrine, Justin Rehwaldt, Akash Bindal, Gordon Mills, Joe Gray, Wassana Yantasee |
| Rok vydání: |
2022 |
| Popis: |
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 developed a nanoparticle-based immunotherapy termed ARAC (Antigen Release Agent and Checkpoint Inhibitor) 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 positive feedback manner. ARAC reduced effective doses of volasertib and PD-L1 antibody by 5-fold in a metastatic lung tumor model (LLC-JSP) and the effect was mainly mediated by CD8 + T cells. Notably, ARAC also showed efficacy in another lung tumor model (KLN-205), which does not respond to CTLA-4 and PD-1 inhibitor combination. Further, the nanoparticle construct was well-tolerated in non-human primates. This study highlights a rationale combination strategy to augment existing therapies by utilizing our nanoparticle platform that can load multiple cargo types at once. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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