Immunotherapy Strategy Targeting Programmed Cell Death Ligand 1 and CD73 with Macrophage-Derived Mimetic Nanovesicles to Treat Bladder Cancer

Abstract

Combination immunotherapy is a promising strategy to remove the inhibitory effect of the tumor microenvironment on immune effector cells, improving the efficacy of immune checkpoint inhibitor treatment in bladder cancer. However, it is challenging to deliver multiple drugs to the tumor tissue effectively and simultaneously to ensure optimal therapeutic effects. Macrophage-derived exosome-mimetic nanovesicles (EMVs) were designed and validated as a nanoplatform for coloading and delivery of the CD73 inhibitor (AB680) and the monoclonal antibody to programmed cell death ligand 1 (aPDL1). The tumor-targeting, biosafety, and therapeutic effects of these nanocomplexes (AB680@EMVs-aPDL1), as a combined immunotherapy strategy for bladder cancer, were assessed in vitro and in vivo. Our results indicate that the nanodrug system was highly stable, provided adequate biosafety, and enhanced tumor targeting in a mouse model of bladder cancer. Moreover, the CD73 inhibitor reduced extracellular adenosine production, and the combination therapy significantly promoted the activation and infiltration of cytotoxic T-lymphocytes, which helped to optimally suppress tumor growth and extend median survival in vivo. Therefore, using EMVs to deliver a combination of aPDL1 and the CD73 inhibitor may be a useful combined immunotherapy strategy for treating bladder cancer.

Macrophage Cell Membrane‐Cloaked Nanoplatforms for Biomedical Applications

“…[ 82 ] These macrophage‐derived nanovesicles preserve the protein content of natural exosomes as well as their intrinsic targeting property to tumor tissues, while providing a superior production yield. [ 82 ]…”

“…[81] In another study, the tumor-targeting capability of macrophagederived exosome-mimetic nanovesicles was harnessed to codeliver AB680 (a small molecule CD73 inhibitor) and the monoclonal antibody against programmed cell death ligand 1 (PDL1, an immune checkpoint inhibitor) for targeted immunotherapy for bladder cancer. [82] These macrophage-derived nanovesicles preserve the protein content of natural exosomes as well as their intrinsic targeting property to tumor tissues, while providing a superior production yield. [82] Another promising strategy to address the aforementioned shortcomings of EVs is the use of hybrid exosomes.…”

“…[82] These macrophage-derived nanovesicles preserve the protein content of natural exosomes as well as their intrinsic targeting property to tumor tissues, while providing a superior production yield. [82] Another promising strategy to address the aforementioned shortcomings of EVs is the use of hybrid exosomes. These entities are prepared by fusing macrophage-derived exosomes with synthetic liposomes through membrane extrusion.…”

Exosome-based drug delivery systems and their therapeutic applications

“…Zhou et al synthesized an anti-PD-L1 (aPD1) modified exosome as an immunotherapy agent. 78 First, the authors conjugated aPD1 with NHS-functionalized PEG (aPD1-PEG). Next, macrophage-derived exosome-mimetic nanovesicles (EMVs) were mixed with aPD1-PEG for 2 h. Interestingly, AB680 was also encapsulated into the EMVs by a mini extruder in order to inhibit CD73, which is related to the activation of tumor reactive T-cells and natural killer cells ( Fig.…”

“…Reprinted with permission. 78 Copyright 2020, American Chemical Society. In a previous study, the surface of an exosome was also functionalized with an anti-cancer drug by a streptavidin (strep)-biotin coupling reaction.…”