Cisplatin nanoparticles possess stronger anti-tumor synergy with PD1/PD-L1 inhibitors than the parental drug

Abstract

Programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) inhibitors provide an evolution in the field of cancer therapy. This results in unprecedented rates of long-lasting tumor responses, once cancer patients respond to PD1/PD-L1 inhibitors. However, the response rate of most cancers is not greater than 30%, which results in a limited therapeutic efficacy. Therefore, the increase of the therapeutic efficacy of PD1/PD-L1 inhibitors is of utmost importance. Hence, this study demonstrated that the sustained increase of tumor PD-L1 levels induced by long-tumor retaining cisplatin (Cis) nanoparticles improved the therapeutic outcomes of PD1/PD-L1 inhibitors. Cis-loaded poly(_L-glutamic acid)-graft-methoxy poly(ethylene glycol) complex nanoparticle (Cisplatin nanoparticle, P-Cis) caused tumor PD-L1 overexpression in a time dependent manner in vitro and amplified tumor PD-L1 signals at 72 h post treatment in vivo. Synergistic tumor inhibition was achieved when P-Cis was combined with PD1/PD-L1 inhibitors, such as BMS-202 and anti-PD1 antibody (aPD1), and a significantly superior tumor inhibition rate was observed in the combination group (P-Cis plus aPD1). In addition, when mice were treated with a single dose of P-Cis plus aPD1, its synergistic anti-tumor effect was much stronger than that of a single dose of Cis plus aPD1, as their Q values were 1.15 and 1.05 in the Lewis lung carcinoma (LLC) tumor model, and 1.92 and 0.95 in the B16F10 tumor model, respectively. The single dose of P-Cis could increase tumor PD-L1 expression at 72 h post injection, while a single-dose of Cis did not, thus the sustained tumor PD-L1 overexpression induced by P-Cis was essential for enhancing aPD1 therapy. The sustained tumor PD-L1 overexpression highlighted the involvement of PD1/PD-L1 pathway in tumor cell proliferation and CD8⁺ T cell weakening and increased the role and possibility of PD1/PD-L1 inhibitors to block the PD1/PD-L1 pathway. Collectively, this study identified a potential clinical treatment with P-Cis plus PD1/PD-L1 inhibitors. STATEMENT OF SIGNIFICANCE: Programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) inhibitors provide an evolution in the field of cancer therapy. However, the response rate of most cancers is not greater than 30%, which results in a limited therapeutic efficacy. Therefore, the increase of the therapeutic efficacy of PD1/PD-L1 inhibitors is of utmost importance. Here, Cisplatin (Cis) loaded poly(_L-glutamic acid)-graft-methoxy poly(ethylene glycol) complex nanoparticle (P-Cis) is found to improve the therapeutic outcomes of PD1/PD-L1 inhibitors via sustained increase of tumor PD-L1 levels, and P-Cis possesses stronger anti-tumor synergy with PD1/PD-L1 inhibitors than the parental drug. This identifies a potential clinical treatment with P-Cis plus PD1/PD-L1 inhibitors.

Keywords: Cisplatin; Combination treatment; Nanomedicine; PD1/PD-L1 inhibitors; Tumor immunotherapy.