Archive | 2021
Development of novel immunotherapy based on nanoparticle co-delivering PLK1 and PD-L1 inhibitors for lung cancer treatment
Abstract
\n 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 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 and the effect was mainly mediated by CD8\u2009+\u2009T cells. We also observed abscopal effect of ARAC in bilateral NSCLC tumor model and achieved complete cures in some mice when incorporating immune-stimulant CpG onto ARAC. Further, ARAC 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.