Extracellular Vesicles and Their Current Role in Cancer Immunotherapy

Abstract

Extracellular vesicles (EVs) are natural particles formed by the lipid bilayer and released from almost all cell types to the extracellular environment both under physiological conditions and in presence of a disease. EVs are involved in many biological processes including intercellular communication, acting as natural carriers in the transfer of various biomolecules such as DNA, various RNA types, proteins and different phospholipids. Thanks to their transfer and targeting abilities, they can be employed in drug and gene delivery and have been proposed for the treatment of different diseases, including cancer. Recently, the use of EVs as biological carriers has also been extended to cancer immunotherapy. This new technique of cancer treatment involves the use of EVs to transport molecules capable of triggering an immune response to damage cancer cells. Several studies have analyzed the possibility of using EVs in new cancer vaccines, which represent a particular form of immunotherapy. In the literature there are only few publications that systematically group and collectively discuss these studies. Therefore, the purpose of this review is to illustrate and give a partial reorganization to what has been produced in the literature so far. We provide basic notions on cancer immunotherapy and describe some clinical trials in which therapeutic cancer vaccines are tested. We thus focus attention on the potential of EV-based therapeutic vaccines in the treatment of cancer patients, overviewing the clinically relevant trials, completed or still in progress, which open up new perspectives in the fight against cancer.

Keywords: cancer vaccine; drug delivery; extracellular vesicles; gene delivery; immunotherapy; nanoparticles; surface funzionalization.

Figure 1

Extracellular vesicles biogenesis and a specific focus on exosome composition. Exosomes originate intracellularly as intraluminal vesicles of the multivesicular bodies; microvesicles originate from the outwards budding and fission of plasma membrane; apoptotic bodies are caused by the fragmentation of the apoptotic cells. The exosomes membrane is composed by different kinds of lipids and proteins and they can carry inside cytosol-derived molecules, such as proteins and nucleic acids.

Figure 2

EVs applications in cancer immunotherapy. (1) Scheme of EVs as cargos of siRNAs, drugs and monoclonal antibodies and (a) therapeutic effect on tumor growth rate of anti-PD-1 and tMNV-directed therapy targeting B-catenin. Reproduced from [117] with the permission of Jhon Wiley and Sons. p-Values as indicated, one-way ANOVA analysis. (2) Scheme of EVs-mediated T-cell activation and (b) data analysis of CD69, a T-cell activation marker on CD4+ and CD8+ T cells following incubation with different exosomes formulations. Reproduced from [109] with permission of Elsevier. * p < 0.05, ** p < 0.01, *** p < 0.001, one-way ANOVA analysis. (3) Scheme of EVs vaccination and (c) tumor specific cytotoxic activity of the combination therapy involving exosomal vaccine and tumor cell vaccine against prostate cancer cells. Reproduced from [110] with permission of John Wiley and Sons. (4) Scheme of DC-pulsed EVs and (d) proliferative response of CD8+ T cells co-cultured with EXOOVA (10 μg/mL), DCOVA, mDCEXO and imDCEXO (3 × 10⁴ cells/well), determined by (3H)thymidine uptake assay after two days. Reproduced from [111] with permission of Jhon Wiley and Sons.