Figures & data
Table 1 Overview of the application of exosomes as a nanoscale cancer vaccine
Figure 1 Biological delivery systems. A) Bacteria can be used for gene delivery, and it is used in cancer gene therapy, DNA vaccination, and treatment of some genetic diseases. B) Bacteriophages are viruses that infect bacteria, and they can be genetically engineered and introduced into bacteria for genetic replication. C) Virus-like particles (VLPs) can be engineered from plasmids coding for viral structure proteins. These VLPs can then be linked to antigens and introduced into the body to elicit an immune response. D) Erythrocyte ghosts are red blood cells that have their cytoplasmic contents removed, and they can be used as vehicles for drug delivery. E) Exosomes are nanoscale vesicles released from dendritic cells and tumor cells, and they can be purified and loaded with antigens and introduced into the body to elicit a cell-specific antitumor response. Copyright © 2009, Nature Publishing Group. Reproduced with permission from Seow Y, Wood MJ. Biological gene delivery vehicles: beyond viral vectors. Mol Ther. 2009;17(5):767–777.
Figure 2 Different functions of immature and mature dendritic cells. A) In the absence of inflammation and costimulation, antigen presentation to immature dendritic cells induces tolerance or anergy (lack of an immune response). This results in deletion or induction of a regulatory phenotype of T cells. B) In the presence of inflammation, immature dendritic cells become activated into mature dendritic cells. Antigen presentation in the presence of costimulatory molecules causes clonal expansion of CD4+ (helper) and CD8+ (cytotoxic) T cells and activation of B cells to produce antibodies and NK cells. Copyright © 2005, Nature Publishing Group. Reproduced with permission from Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol. 2005;5(4):296–306.
Figure 3 Interactions of exosomes and other nanoscale vesicles with cells of the immune system. A) A variety of cells secrete exosomes, and it can activate different types of immune cells, mainly via antigen presentation. B) Exosomes can also have an inhibitory effect on the immune system, although the mechanisms are not well understood. Copyright © 2009, Nature Publishing Group. Reproduced with permission from Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581–593.
Figure 4 The therapeutic application of AEX. Dendritic cells from peripheral blood monocytes are pulsed with AEX, and cell-specific anti tumor response has been observed. Copyright © 2002, Elsevier. Reproduced with permission from Andre F, Schartz NE, Movassagh M, et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet. 2002;360(9329):295–305.
Figure 5 Exosomes are observed on the surface of glioblastoma cells. Tumor-specific peptides or antigens from TEX can be purified and pulsed onto dendritic cells for immunotherapy. Copyright © 2008, Nature Publishing Group. Reproduced with permission from Skog J, Wurdinger T, van Rijn S, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470–1476.
Figure 6 Clinical grade exosomes in immunotherapy. The process of how DEX can be derived, purified, and utilized in cancer treatment. Creative Commons. Reproduced with permission from Escudier B, Dorval T, Chaput N, et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J Transl Med. 2005;3(1):10.
Table 2 The application of exosomes as a cancer vaccine in Phase I clinical trials
Figure 7 Carbon nanotubes in cancer immunotherapy. A) Pristine CNT is the default setting of CNT, which lacks any bioconjugation or biofunctionalization. They have a strong tendency to aggregate and are mostly used in studies to assess nanotoxicity. B) PEG-conjugated CNT can be used in systemic cancer imaging. C) Copolymer or surfactant-coated CNT with PEO or PPO, and it can be used in localized cancer imaging. D) ssDNA-coated CNT, which aids dispersion and separation. E) Chemically functionalized (covalent surface modification) CNT by 1,3 dipolar cycloaddition. F) Chemically functionalized (covalent surface modification) CNT by acid oxidation. Copyright © 2009, Nature Publishing Group. Reproduced with permission from Kostarelos K, Bianco A, Prato M. Promises, facts and challenges for carbon nanotubes in imaging and therapeutics. Nat Nanotechnol. 2009;4(10):627–633.
Abbreviations: CNT, carbon nanotube; PEG, lipid-polyethylene glycol; PEO, polyethylene oxide; PPO, polypropylene oxide; ssDNA, single-stranded DNA.
Figure 8 Interaction of engineered exosomes with cells of the immune system. A) Engineered exosomes (red small circles) coated with A2*MHC class I molecules bound to CMV peptides do not bind CD8+ T cell (stained green) from a CMV positive donor who is HLA A2 negative, showing that exosomes do not bind randomly to T cells and that binding is very much MHC dependant. B) However, when the same exosomes carrying A2*MHC/CMV complexes are cocultured with T cell from a CMV+ and A2+ donor, direct interaction between exosomes and CD8+ T cells is clearly seen. C) Engineered exosomes (stained red) also bind to natural APCs (stained green and orange when the red and green color overlaps). This figure shows a natural APC activating three different CD8 T cells via engineered exosomes. D) Exosomes bind to APC naturally whether they are engineered or not as the lipids themselves are the binding sites. Copyright © 2009, Nature Publishing Group. de La Pena H, Madrigal JA, Rusakiewicz S, et al. Artificial exosomes as tools for basic and clinical immunology. J Immunol Methods. 2009;344(2):121–132.
