Abstract
Immune checkpoint receptor signaling pathways constitute a prominent class of “immune synapse,” a cell-to-cell connection that represses T-lymphocyte effector functions. As a possible evolutionary countermeasure against autoimmunity, this strategy is aimed at lowering potential injury to uninfected cells in infected tissues and at minimizing systemic inflammation. Nevertheless, tumors can make use of these strategies to escape immune recognition, and consequently, such mechanisms represent chances for immunotherapy intervention. Recent years have witnessed the advance of pharmaceutical nanotechnology, or nanomedicine, as a possible strategy to ameliorate immunotherapy technical weaknesses thanks to its intrinsic biophysical properties and multifunctional modifying capability. To improve the long-lasting response rate of checkpoint blockade therapy, nanotechnology has been employed at first for the delivery of single checkpoint inhibitors. Further, while therapy via single immune checkpoint blockade determines resistance and a restricted period of response, strong interest has been raised to efficiently deliver immunomodulators targeting different inhibitory pathways or both inhibitory and costimulatory pathways. In this review, the partially explored promise in implementation of nanotechnology to improve the success of immune checkpoint therapy and solve the limitations of single immune checkpoint inhibitors is debated. We first present the fundamental elements of the immune checkpoint pathways and then outline recent promising results of immune checkpoint blockade therapy in combination with nanotechnology delivery systems.
Highlights
Immunotherapy is a modern branch of oncotherapy modulating immune system activity against cancer
Nanoparticles (NPs) are designed in multiple ways, thanks to their plasticity in composition, geometry and size and may be useful to overcome critical points of ICI. Therapy, such as the localized and controlled ICI release, availability and ICI stability after infusion; further, they may allow for a reduction of ICI dose and control over adverse immune-related events (AIEs)
Another study investigating the use of pembrolizumab in combination with a variety of options of chemotherapy in the upfront treatment of triple negative metastatic breast cancer patients, the Keynote-355 study, reported a significant improvement in terms of progression-free survival in the PD-ligand 1 (PD-L1)-positive subgroup that seemed relevant when the anti-PD-1 was associated with taxane-based regimens, largely consisting in nab-paclitaxel [132]
Summary
Immunotherapy is a modern branch of oncotherapy modulating immune system activity against cancer. In the case of immune-competent tumors like non-small-cell lung cancer or melanoma, where ICI efficacy is clinically relevant, some patients are not sensitive at all to this approach, and others experience disease progression after an initial, more or less durable response. This is due to the high levels of inter- and intra-tumor variability with regard to multiple mechanisms of primary and acquired resistances, such as inefficient antigen presentation, poor T-cell infiltration and tumor mutational burden [11,12,13]. We summarize preclinical studies proposing this approach, focusing on CTLA-4 and PD-1/PD-L1 blockade therapy, both as single agents and in combination strategies
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