PD-L1 and PD-1 are immune checkpoints that control signal pathways associated with T-cell activation. Previously, scientists targeted the PD-1/PD-L1 axis with immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC).
Study: Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment. Image Credit: Julia Lazebnaya/Shutterstock.com
This study showed that only an insignificant number of NSCLC patients benefitted from this treatment. Researchers addressed this shortcoming and formulated a nanoparticle-based immunotherapy, called ARAC (Antigen Release Agent and Checkpoint Inhibitor), which enhanced the efficacy of PD-L1 inhibitors against lung cancer. This study has been published in Nature Communications.
Immune Checkpoint Inhibitors and Lung Cancer Treatment
Scientists stated that the discovery of ICSs, particularly the development of antibodies targeting PD-L1 and PD-1, has altered the pathway of cancer treatments, including NSCLC. Studies have shown that PD-L1 expression on tumor cells causes inhibition of the cytotoxic activity of CD8+ T cells. Hence, PD-1/PD-L1 overexpression serves as a marker for an immunosuppressive environment that occurs during various types of cancer.
Although PD-1/PD-L1 inhibitors were effective against lung cancer patients, only a small percentage of patients responded to them. Additionally, some of the initial responders showed relapse of the disease, indicating the development of a resistance mechanism.
Previous studies have reported that a high concentration of PD-L1 has been linked with better treatment outcomes. Similarly, a decrease in the concentration of tumor-infiltrating lymphocytes (TILs) was linked with ineffective ICI treatment or even resistance. Scientists believe that a combination therapy using PD-L1/PD-1 inhibitors and other therapeutics that enhance PD-L1 expression and TILs density could significantly elevate the response rate of treatments.
Previous studies have reported that polo-like kinase 1 (PLK1), a mitotic kinase, is overexpressed during many types of cancers. Although several PLK1 small molecule inhibitors are being evaluated for cancer treatment, initial reports have suggested poor efficacy as a monotherapy. Hence, there is a need to develop an alternate strategy to realize the full capacity of PLK1 inhibitors.
PLK1 Inhibitor for Lung Cancer Treatment
PLK1 expression triggers signal transducer and activator of transcription 3 (STAT3), which facilitates immunosuppressive tumor microenvironment (TME). Hence, PLK1inhibitor can reduce phosphorylation of STAT3 and decrease its function in NSCLC cells. Prior research using multiple cell lines reported that PLK1 inhibition elevated MHC class I expression, indicating activation of adaptive immunity.
Although the effectiveness of PLK1 inhibitors against various types of cancer is well documented, the relationship between PLK1 inhibition and cancer immunity is not well understood. The new study reported that PLK1 inhibition causes an increment of PD-L1 expression in cancer cells. In lung cancer patients, PLK1 inhibition triggered the upregulation of PD-L1 via the mitogen-activated protein kinase (MAPK) pathway.
The upregulation of PD-L1 indicated that cancer cells that survive PLK1 inhibition exploit mechanisms that facilitate evasion of immune responses. The current study revealed that the combinational therapy using PLK1 inhibitor and PD-L1 antibody could considerably decrease the tumor progression in mice compared to monotherapies.
Development of Nanoparticle-based Immunotherapy
Scientists utilized nanoparticles to overcome the dose-limiting toxicity of current PLK1 inhibitors that prevented them from advancing beyond clinical trials. To obtain a synergistic effect of PLK1 inhibition and PD-L1 blockade, scientists synthesized a PLK1 inhibitor-loaded nanoparticle and conjugated it into a PD-L1 antibody (ARAC).
Previous in vivo studies by the same group of researchers revealed that this nanoparticle platform could safely and effectively deliver siRNA, which could facilitate gene knockdown of breast and lung tumors. In this study, volasertib (iPLK1) was loaded in mesoporous silica nanoparticle (MSNP) core, which was subsequently subjected to surface modification with polyethylene glycol (PEG), polyethylenimine (PEI), and PD-L1 antibody. The sol-gel MSNP synthesis and systemically layer-by-layer modification significantly enhanced the reproducibility and scalability of AARC.
The authors incorporated PEI and PEG to prevent nanoparticles from aggregation during antibody loading. Scientists estimated the rigid core size and hydrodynamic size of volasertib-loaded nanoparticles. They reported that drug-loaded nanoparticles with PD-L1 antibody (ARAC) and without (iPLK1-NP) exhibited a core size of 50 nm and hydrodynamic size of 90 nm.
The loaded nanoparticle could be stored at −80oC without affecting its size and function. The present study reported that volasertib could be selectively released from nanoparticles in endo/lysosomal solution (pH 4.5), compared to control cells (PBS) at pH 7.4.
Efficacy of Nanoparticle-Based Immunotherapy Against Lung Cancer
Scientists reported that compared to free PLK1 inhibitor the newly developed nanoparticle-based immunotherapy could significantly enhance the delivery of volasertib and reduce the viability of lung tumor cells. Analysis of co-delivered PLK1 inhibitor and PD-L1 antibody as free drugs as well as in a nanoparticle platform showed contrasting results. Nano-based ARAC treatment effectively reduced lung tumors compared to free drugs.
The authors reported that ARAC could significantly decrease PD-L1 expression in both immune and cancer cells. Additionally, it can effectively elevate the number of CD8+ in lung tumor cells infiltrating lymphocytes, along with the CD8+/Tregs ratio. This finding strongly indicates that the new treatment can change the tumor microenvironment to an immune-permissive condition.
The lung tumor model also showed that ARAC therapy overcomes the dose-limiting toxicity related to PLK1 inhibitors. Importantly, ARAC treatment showed significant efficacy in the ICI-refractory tumor model with an enhanced survival rate in mice.
Reference
Reda, M. et al. (2022) Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment. Nature Communications, 13, 4261. https://www.nature.com/articles/s41467-022-31926-9
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