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Dendritic cell–derived exosomes for cancer therapy
Jonathan M. Pitt, … , Guido Kroemer, Laurence Zitvogel
Jonathan M. Pitt, … , Guido Kroemer, Laurence Zitvogel
Published April 1, 2016
Citation Information: J Clin Invest. 2016;126(4):1224-1232. https://doi.org/10.1172/JCI81137.
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Review Series

Dendritic cell–derived exosomes for cancer therapy

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Abstract

DC-derived exosomes (Dex) are nanometer-sized membrane vesicles that are secreted by the sentinel antigen-presenting cells of the immune system: DCs. Like DCs, the molecular composition of Dex includes surface expression of functional MHC-peptide complexes, costimulatory molecules, and other components that interact with immune cells. Dex have the potential to facilitate immune cell–dependent tumor rejection and have distinct advantages over cell-based immunotherapies involving DCs. Accordingly, Dex-based phase I and II clinical trials have been conducted in advanced malignancies, showing the feasibility and safety of the approach, as well as the propensity of these nanovesicles to mediate T and NK cell–based immune responses in patients. This Review will evaluate the interactions of Dex with immune cells, their clinical progress, and the future of Dex immunotherapy for cancer.

Authors

Jonathan M. Pitt, Fabrice André, Sebastian Amigorena, Jean-Charles Soria, Alexander Eggermont, Guido Kroemer, Laurence Zitvogel

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Figure 2

The GMP manufacturing of Dex immunotherapy.

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The GMP manufacturing of Dex immunotherapy.
Leukapheresis is performed f...
Leukapheresis is performed for advanced cancer patients who will undergo Dex therapy. Within a cell therapy unit GMP (good manufacturing practices) laboratory, monocytes are isolated following elutriation, and these are differentiated to immature DCs (iDC) by addition of GM-CSF and IL-4 in culture. iDCs may then undergo a quality control (QC) check before loading of MHC-I– and MHC-II–binding peptides in the presence of IFN-γ to generate mDC. Peptide-loaded exosomes from culture supernatants can then be isolated and concentrated by a process of centrifugation, diafiltration, and finally ultracentrifugation over a D2O sucrose gradient. QC testing of immunological characteristics (e.g., tetraspanin content of Dex, MHC-II and costimulatory molecule levels) and immunostimulatory capacity (e.g., ability to stimulate a peptide-cognate T cell clone) is then performed for each preparation to determine whether a given batch can be released. Released batches may then be stored (–80°C) for therapeutic administration through intradermal (i.d.) injections. Production of Dex for immunotherapy takes approximately three weeks from the initial leukapheresis (this includes time for Dex manufacturing, QC testing, and treatment of the patient with metronomic cyclophosphamide).
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