Exosomes in Cancer Nanomedicine and Immunotherapy: Prospects and Challenges.

Exosomes (versatile, cell-derived nanovesicles naturally endowed with exquisite target-homing specificity and the ability to surmount in vivo biological barriers) hold substantial promise for developing exciting approaches in drug delivery and cancer immunotherapy. Specifically, bioengineered exosomes are being successfully deployed to deliver potent tumoricidal drugs (siRNAs and chemotherapeutic compounds) preferentially to cancer cells, while a new generation of exosome-based therapeutic cancer vaccines has produced enticing results in early-phase clinical trials. Here, we review the state-of-the-art technologies and protocols, and discuss the prospects and challenges for the clinical development of this emerging class of therapeutics.

[1]  L. Zitvogel,et al.  Updated Technology to Produce Highly Immunogenic Dendritic Cell-derived Exosomes of Clinical Grade: A Critical Role of Interferon-&ggr; , 2011, Journal of immunotherapy.

[2]  L. Gurevich,et al.  Evaluation of electroporation-induced adverse effects on adipose-derived stem cell exosomes , 2016, Cytotechnology.

[3]  S. Gabrielsson,et al.  Dendritic Cell–Derived Exosomes Need To Activate Both T and B Cells To Induce Antitumor Immunity , 2013, The Journal of Immunology.

[4]  F. Vannberg,et al.  Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node , 2016, Scientific Reports.

[5]  Laurence Zitvogel,et al.  Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming , 2001, Nature Medicine.

[6]  J. Aerts,et al.  Tumour-derived exosomes as antigen delivery carriers in dendritic cell-based immunotherapy for malignant mesothelioma , 2013, Journal of extracellular vesicles.

[7]  A. Khvorova,et al.  High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources , 2016, Journal of extracellular vesicles.

[8]  A. Molinari,et al.  Immune Surveillance Properties of Human NK Cell-Derived Exosomes , 2012, The Journal of Immunology.

[9]  S. Jay,et al.  Oncogene Knockdown via Active Loading of Small RNAs into Extracellular Vesicles by Sonication , 2016, Cellular and molecular bioengineering.

[10]  Mehmet Fatih Bolukbasi,et al.  Genetically Engineered Microvesicles Carrying Suicide mRNA/Protein Inhibit Schwannoma Tumor Growth , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[11]  R. Ramesh,et al.  Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells , 2016, Scientific Reports.

[12]  Silvia Maria Doglia,et al.  Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[13]  Jin Ding,et al.  Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA. , 2016, Cancer cell.

[14]  Elisabetta Vergani,et al.  TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site , 2016, Clinical Cancer Research.

[15]  J. Barbuto,et al.  Dendritic Cell-Derived Exosomes may be a Tool for Cancer Immunotherapy by Converting Tumor Cells into Immunogenic Targets , 2015, Front. Immunol..

[16]  Zhongdang Xiao,et al.  Dynamics of exosome internalization and trafficking , 2013, Journal of cellular physiology.

[17]  Joo Chuan Yeo,et al.  Microfluidic size separation of cells and particles using a swinging bucket centrifuge. , 2015, Biomicrofluidics.

[18]  R. Nieuwland,et al.  Handling and storage of human body fluids for analysis of extracellular vesicles , 2015, Journal of extracellular vesicles.

[19]  V. Canzonieri,et al.  Exosomal doxorubicin reduces the cardiac toxicity of doxorubicin. , 2015, Nanomedicine.

[20]  S. Madlener,et al.  Extracellular vesicle-mediated suicide mRNA/protein delivery inhibits glioblastoma tumor growth in vivo , 2016, Cancer Gene Therapy.

[21]  Olivier Lantz,et al.  Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial , 2005, Journal of Translational Medicine.

[22]  Ashish Kumar Agrawal,et al.  Exosomal formulation enhances therapeutic response of celastrol against lung cancer. , 2016, Experimental and molecular pathology.

[23]  Carl Virtanen,et al.  Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: the Princess Margaret IMPACT/COMPACT trial , 2016, Genome Medicine.

[24]  Weiying Zhou,et al.  Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. , 2014, Cancer cell.

[25]  Laurence Zitvogel,et al.  Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes , 1998, Nature Medicine.

[26]  S. Gabrielsson,et al.  Potentiating antitumor immunity with αGC-loaded exosomes , 2013, Oncoimmunology.

[27]  Qiyu Zhao,et al.  Increased anti-tumour activity by exosomes derived from doxorubicin-treated tumour cells via heat stress , 2015, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[28]  F. Sánchez‐Madrid,et al.  Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs , 2013, Nature Communications.

[29]  J. Dranoff,et al.  Extracellular vesicles carry microRNA‐195 to intrahepatic cholangiocarcinoma and improve survival in a rat model , 2017, Hepatology.

[30]  T. Janas,et al.  Mechanisms of RNA loading into exosomes , 2015, FEBS letters.

[31]  Gary K. Schwartz,et al.  Tumour exosome integrins determine organotropic metastasis , 2015, Nature.

[32]  J. Hubbell,et al.  TLR-3 stimulation improves anti-tumor immunity elicited by dendritic cell exosome-based vaccines in a murine model of melanoma , 2015, Scientific Reports.

[33]  Jun Yao,et al.  Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth , 2015, Nature.

[34]  K. Braeckmans,et al.  Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[35]  Tianzhi Yang,et al.  Exosome Delivered Anticancer Drugs Across the Blood-Brain Barrier for Brain Cancer Therapy in Danio Rerio , 2014, Pharmaceutical Research.

[36]  Kit Lam,et al.  Single exosome study reveals subpopulations distributed among cell lines with variability related to membrane content , 2015, Journal of extracellular vesicles.

[37]  Steven M Jay,et al.  Exogenous DNA Loading into Extracellular Vesicles via Electroporation is Size-Dependent and Enables Limited Gene Delivery. , 2015, Molecular pharmaceutics.

[38]  M. Eldh,et al.  Exosomal cancer immunotherapy is independent of MHC molecules on exosomes , 2016, Oncotarget.

[39]  C. Fenselau,et al.  Surface Glycoproteins of Exosomes Shed by Myeloid-Derived Suppressor Cells Contribute to Function. , 2017, Journal of proteome research.

[40]  Imre Mäger,et al.  Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting , 2015, Journal of extracellular vesicles.

[41]  S. Kondo,et al.  Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes , 2014, Oncogene.

[42]  R. Schiffelers,et al.  PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[43]  M. Büchler,et al.  Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice , 2015, International journal of cancer.

[44]  Olivier Lantz,et al.  Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC , 2015, Oncoimmunology.

[45]  Susanne Gabrielsson,et al.  Synergistic induction of adaptive antitumor immunity by codelivery of antigen with α-galactosylceramide on exosomes. , 2013, Cancer research.

[46]  Laurence Zitvogel,et al.  Dendritic Cell-Derived Exosomes Promote Natural Killer Cell Activation and Proliferation: A Role for NKG2D Ligands and IL-15Rα , 2009, PloS one.

[47]  A. Möller,et al.  Optimized exosome isolation protocol for cell culture supernatant and human plasma , 2015, Journal of extracellular vesicles.

[48]  H. Ishitobi,et al.  Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration. , 2014, Biochemical and biophysical research communications.

[49]  I. Sargent,et al.  Exosome-mediated delivery of siRNA in vitro and in vivo , 2012, Nature Protocols.

[50]  R. Pink,et al.  Routes and mechanisms of extracellular vesicle uptake , 2014, Journal of extracellular vesicles.

[51]  Shinobu Ueda,et al.  Systemically Injected Exosomes Targeted to EGFR Deliver Antitumor MicroRNA to Breast Cancer Cells. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[52]  S. Gabrielsson,et al.  Cancer immunotherapy with exosomes requires B-cell activation , 2013, Oncoimmunology.

[53]  Jian Song,et al.  A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. , 2014, Biomaterials.

[54]  S. Lim,et al.  Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. , 2013, Advanced drug delivery reviews.

[55]  Heikki Saari,et al.  Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[56]  Ji-Ho Park,et al.  Liposome-based engineering of cells to package hydrophobic compounds in membrane vesicles for tumor penetration. , 2015, Nano letters.

[57]  C. Coch,et al.  RIG-I activation induces the release of extracellular vesicles with antitumor activity , 2016, Oncoimmunology.

[58]  Myung Soo Kim,et al.  Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. , 2016, Nanomedicine : nanotechnology, biology, and medicine.

[59]  Hakho Lee,et al.  Acoustic purification of extracellular microvesicles. , 2015, ACS nano.

[60]  B. Goh,et al.  Evolving landscape of tumor molecular profiling for personalized cancer therapy: a comprehensive review , 2016, Expert opinion on drug metabolism & toxicology.

[61]  J. Redzic,et al.  Examination of the specificity of tumor cell derived exosomes with tumor cells in vitro. , 2014, Biochimica et biophysica acta.

[62]  C. Chen,et al.  Elevated aflatoxin exposure and increased risk of hepatocellular carcinoma , 1996, Hepatology.

[63]  C. Genoud,et al.  Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER , 2016, The Journal of cell biology.

[64]  Jennifer C Jones,et al.  Efficient production and enhanced tumor delivery of engineered extracellular vesicles. , 2016, Biomaterials.

[65]  G. Stolovitzky,et al.  Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. , 2016, Nature nanotechnology.

[66]  L. Zitvogel,et al.  Dendritic cell-derived exosomes for cancer therapy. , 2016, The Journal of clinical investigation.

[67]  Xin Hou,et al.  Blood Exosomes Endowed with Magnetic and Targeting Properties for Cancer Therapy. , 2016, ACS nano.

[68]  Biana Godin,et al.  Ciliated micropillars for the microfluidic-based isolation of nanoscale lipid vesicles. , 2013, Lab on a chip.

[69]  J. Sluijter,et al.  Presence of Cx43 in extracellular vesicles reduces the cardiotoxicity of the anti-tumour therapeutic approach with doxorubicin , 2016, Journal of extracellular vesicles.

[70]  J. Xiang,et al.  Intradermal vaccination of dendritic cell-derived exosomes is superior to a subcutaneous one in the induction of antitumor immunity. , 2006, Cancer biotherapy & radiopharmaceuticals.

[71]  Andrew F. Hill,et al.  Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper , 2015, Journal of extracellular vesicles.

[72]  George A Calin,et al.  Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. , 2014, Cancer cell.

[73]  Kwang Ryeol Lee,et al.  Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein–protein interaction module , 2016, Nature Communications.

[74]  Razelle Kurzrock,et al.  Association of Biomarker-Based Treatment Strategies With Response Rates and Progression-Free Survival in Refractory Malignant Neoplasms: A Meta-analysis. , 2016, JAMA oncology.

[75]  Pieter Vader,et al.  Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting , 2016, Journal of extracellular vesicles.

[76]  K. Jensen,et al.  In vitro and ex vivo strategies for intracellular delivery , 2016, Nature.

[77]  William J. Buchser,et al.  Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands , 2012, Oncoimmunology.

[78]  J. Le Pecq,et al.  A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer , 2005, Journal of Translational Medicine.

[79]  A. J. Tavares,et al.  Analysis of nanoparticle delivery to tumours , 2016 .

[80]  J. Thiery,et al.  Exosome-Mediated Metastasis: From Epithelial-Mesenchymal Transition to Escape from Immunosurveillance. , 2016, Trends in pharmacological sciences.

[81]  Flavio Rizzolio,et al.  Exosomes increase the therapeutic index of doxorubicin in breast and ovarian cancer mouse models. , 2016, Nanomedicine.

[82]  Tomoko Ito,et al.  Exosomes derived from tumor cells genetically modified to express Mycobacterium tuberculosis antigen: a novel vaccine for cancer therapy , 2016, Biotechnology Letters.

[83]  T. Anchordoquy,et al.  Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[84]  A. Carracedo,et al.  Different EV enrichment methods suitable for clinical settings yield different subpopulations of urinary extracellular vesicles from human samples , 2016, Journal of extracellular vesicles.