Therapeutic potential of CAR-T cell-derived exosomes: A cell-free modality for targeted cancer therapy

Oncotarget

Volumn 6, Issue 42, 2015, Pages 44179-44190

  Tang, Xiang Jun ^a   Sun, Xu Yong ^b   Huang, Kuan Ming ^a   Zhang, Li ^a   Yang, Zhuo Shun ^a   Zou, Dan Dan ^a   Wang, Bin ^a,c   Warnock, Garth L ^c   Dai, Long Jun ^a,c   Luo, Jie ^a  

^a HUBEI UNIVERSITY OF MEDICINE   (China)

^b The 303rd Hospital of PLA   (China)

^c UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

Cancer therapy; Chimeric antigen receptor (CAR); Exosomes; Extracellular vesicles; Immunotherapy

Indexed keywords

CHIMERIC ANTIGEN RECEPTOR; NANOCARRIER; T LYMPHOCYTE RECEPTOR; CYTOKINE; HYBRID PROTEIN; LYMPHOCYTE ANTIGEN RECEPTOR;

ADOPTIVE IMMUNOTHERAPY; ADOPTIVE TRANSFER; ARTICLE; CANCER GENE THERAPY; CELL COMMUNICATION; CELL EXPANSION; CYTOKINE PRODUCTION; CYTOKINE RELEASE SYNDROME; CYTOKINE STORM; CYTOTOXIC T LYMPHOCYTE; DENDRITIC CELL; EXOSOME; GENETIC ENGINEERING; HEMATOLOGIC MALIGNANCY; HUMAN; MESENCHYMAL STEM CELL; MULTIVESICULAR BODY; NONHUMAN; SOLID TUMOR; ANIMAL; BIOSYNTHESIS; CELL FREE SYSTEM; GENETICS; IMMUNOLOGY; LYMPHOCYTE ACTIVATION; METABOLISM; NEOPLASMS; PROCEDURES; SIGNAL TRANSDUCTION; T LYMPHOCYTE; TRANSPLANTATION;

ANIMALS; CELL-FREE SYSTEM; CYTOKINES; EXOSOMES; GENETIC ENGINEERING; HUMANS; IMMUNOTHERAPY, ADOPTIVE; LYMPHOCYTE ACTIVATION; NEOPLASMS; RECEPTORS, ANTIGEN, T-CELL; RECOMBINANT FUSION PROTEINS; SIGNAL TRANSDUCTION; T-LYMPHOCYTES;

EID: 84953405691     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.6175     Document Type: Article

References (106)

1. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013; 342:1432-1433.
2. Topalian SL, Wolchok JD, Chan TA, Mellman I, Palucka K, Banchereau J, Rosenberg SA and Dane Wittrup K. Immunotherapy: The path to win the war on cancer? Cell. 2015; 161:185-186.
3. Rosenberg SA and Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015; 348:62-68.
4. Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, Morgan RA and Rosenberg SA. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010; 116:4099-4102.
5. Rosenberg SA. Decade in review-cancer immunotherapy: entering the mainstream of cancer treatment. Nat Rev Clin Oncol. 2014; 11:630-632.
6. Johnstone RM, Adam M, Hammond JR, Orr L and Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Bio Chem. 1987; 262:9412-9420.
7. Robbins PD and Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014; 14:195-208.
8. Blanchard N, Lankar D, Faure F, Regnault A, Dumont C, Raposo G and Hivroz C. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol. 2002; 168:3235-3241.
9. Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, Morando L, Busca A, Falda M, Bussolati B, Tetta C and Camussi G. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009; 20:1053-1067.
10. Thery C, Duban L, Segura E, Veron P, Lantz O and Amigorena S. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol. 2002; 3:1156-1162.
11. Muntasell A, Berger AC and Roche PA. T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. EMBO J. 2007; 26:4263-4272.
12. Klinker MW, Lizzio V, Reed TJ, Fox DA and Lundy SK. Human B Cell-Derived Lymphoblastoid Cell Lines Constitutively Produce Fas Ligand and Secrete MHCII(+)FasL(+) Killer Exosomes. Front Immunol. 2014; 5:144.
13. Okoye IS, Coomes SM, Pelly VS, Czieso S, Papayannopoulos V, Tolmachova T, Seabra MC and Wilson MS. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity. 2014; 41:89-103.
14. Lugini L, Cecchetti S, Huber V, Luciani F, Macchia G, Spadaro F, Paris L, Abalsamo L, Colone M, Molinari A, Podo F, Rivoltini L, Ramoni C and Fais S. Immune surveillance properties of human NK cell-derived exosomes. J Immunol. 2012; 189(6):2833-2842.
15. Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakefield XO and Widmark A. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer. 2009; 100:1603-1607.
16. Buschow SI, Nolte-'t Hoen EN, van Niel G, Pols MS, ten Broeke T, Lauwen M, Ossendorp F, Melief CJ, Raposo G, Wubbolts R, Wauben MH and Stoorvogel W. MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic. 2009; 10:1528-1542.
17. Nolte-'t Hoen EN, Buschow SI, Anderton SM, Stoorvogel W and Wauben MH. Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood. 2009; 113:1977-1981.
18. Lai RC, Tan SS, Teh BJ, Sze SK, Arslan F, de Kleijn DP, Choo A and Lim SK. Proteolytic Potential of the MSC Exosome Proteome: Implications for an Exosome-Mediated Delivery of Therapeutic Proteasome. Int J Proteomics. 2012; 2012:971907.
19. Chen TS, Lai RC, Lee MM, Choo AB, Lee CN and Lim SK. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res. 2010; 38:215-224.
20. Simpson RJ, Jensen SS and Lim JW. Proteomic profiling of exosomes: current perspectives. Proteomics. 2008; 8:4083-4099.
21. Schorey JS and Bhatnagar S. Exosome function: from tumor immunology to pathogen biology. Traffic. 2008; 9:871-881.
22. Teo H, Perisic O, Gonzalez B and Williams RL. ESCRT-II, an endosome-associated complex required for protein sorting: crystal structure and interactions with ESCRT-III and membranes. Dev Cell. 2004; 7:559-569.
23. Piper RC and Katzmann DJ. Biogenesis and function of multivesicular bodies. Ann Rev Cell Dev Biol. 2007; 23:519-547.
24. Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Ann Rev Physiol. 2015; 77:13-27.
25. Tran TH, Mattheolabakis G, Aldawsari H and Amiji M. Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases. Clin Immunol. 2015; 160:46-58.
26. Gupta A and Pulliam L. Exosomes as mediators of neuroinflammation. J Neuroinflammation. 2014; 11:68.
27. Peterson MF, Otoc N, Sethi JK, Gupta A and Antes TJ. Integrated systems for exosome investigation. Methods. 2015.
28. Mears R, Craven RA, Hanrahan S, Totty N, Upton C, Young SL, Patel P, Selby PJ and Banks RE. Proteomic analysis of melanoma-derived exosomes by two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Proteomics. 2004; 4:4019-4031.
29. Thery C, Zitvogel L and Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2:569-579.
30. Futter CE and White IJ. Annexins and endocytosis. Traffic. 2007; 8:951-958.
31. Thery C, Boussac M, Veron P, Ricciardi-Castagnoli P, Raposo G, Garin J and Amigorena S. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol. 2001; 166:7309-7318.
32. Segura E, Amigorena S and Thery C. Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses. Blood Cells Mol Dis. 2005; 35:89-93.
33. Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA and Multhoff G. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res. 2005; 65:5238-5247.
34. Clayton A, Harris CL, Court J, Mason MD and Morgan BP. Antigen-presenting cell exosomes are protected from complement-mediated lysis by expression of CD55 and CD59. Eur J Immunol. 2003; 33:522-531.
35. Zwicker JI, Liebman HA, Neuberg D, Lacroix R, Bauer KA, Furie BC and Furie B. Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res. 2009; 15:6830-6840.
36. Saunderson SC, Dunn AC, Crocker PR and McLellan AD. CD169 mediates the capture of exosomes in spleen and lymph node. Blood. 2014; 123:208-216.
37. Wiklander OP, Nordin JZ, O'Loughlin A, Gustafsson Y, Corso G, Mager I, Vader P, Lee Y, Sork H, Seow Y, Heldring N, Alvarez-Erviti L, Smith CE, Le Blanc K, Macchiarini P, Jungebluth P, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015; 4:26316.
38. Thery C. Cancer: Diagnosis by extracellular vesicles. Nature. 2015; 523:161-162.
39. Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D and Kalluri R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015; 523:177-182.
40. Alderton GK. Diagnosis: Fishing for exosomes. Nat Rev Cancer. 2015; 15:453.
41. Zhang X, Yuan X, Shi H, Wu L, Qian H and Xu W. Exosomes in cancer: small particle, big player. J Hematol Oncol. 2015; 8:83.
42. Colombo M, Raposo G and Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014; 30:255-289.
43. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ and Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007; 9:654-659.
44. El Andaloussi S, Lakhal S, Mager I and Wood MJ. Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deli Rev. 2013; 65:391-397.
45. Wood MJ, O'Loughlin AJ and Samira L. Exosomes and the blood-brain barrier: implications for neurological diseases. Ther Deliv. 2011; 2:1095-1099.
46. Yang T, Martin P, Fogarty B, Brown A, Schurman K, Phipps R, Yin VP, Lockman P and Bai S. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm Res. 2015; 32:2003-2014.
47. Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C, Flament C, Pouzieux S, Faure F, Tursz T, Angevin E, Amigorena S and Zitvogel L. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med. 2001; 7:297-303.
48. Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, Pomel C, Lhomme C, Escudier B, Le Chevalier T, Tursz T, Amigorena S, Raposo G, Angevin E and Zitvogel L. Malignant effusions and immunogenic tumour-derived exosomes. Lancet. 2002; 360:295-305.
49. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ and Geuze HJ. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996; 183:1161-1172.
50. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G and Amigorena S. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med. 1998; 4:594-600.
51. Sung BH, Ketova T, Hoshino D, Zijlstra A and Weaver AM. Directional cell movement through tissues is controlled by exosome secretion. Nat Commun. 2015; 6:7164.
52. Afreen S and Dermime S. The immunoinhibitory B7-H1 molecule as a potential target in cancer: killing many birds with one stone. Hematol Oncol Stem Cell Ther. 2014; 7:1-17.
53. Wieckowski EU, Visus C, Szajnik M, Szczepanski MJ, Storkus WJ and Whiteside TL. Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J Immunol. 2009; 183:3720-3730.
54. Yang C and Robbins PD. Immunosuppressive exosomes: a new approach for treating arthritis. Int J Rheumatol. 2012; 2012:573528.
55. Kim SH, Bianco NR, Shufesky WJ, Morelli AE and Robbins PD. Effective treatment of inflammatory disease models with exosomes derived from dendritic cells genetically modified to express IL-4. J Immunol. 2007; 179:2242-2249.
56. Wada J, Onishi H, Suzuki H, Yamasaki A, Nagai S, Morisaki T and Katano M. Surface-bound TGF-beta1 on effusion-derived exosomes participates in maintenance of number and suppressive function of regulatory T-cells in malignant effusions. Anticancer Res. 2010; 30:3747-3757.
57. Gehrmann U, Hiltbrunner S, Georgoudaki AM, Karlsson MC, Naslund TI and Gabrielsson S. Synergistic induction of adaptive antitumor immunity by codelivery of antigen with alpha-galactosylceramide on exosomes. Cancer Res. 2013; 73:3865-3876.
58. Scheerlinck JP and Greenwood DL. Virus-sized vaccine delivery systems. Drug Discov Today. 2008; 13:882-887.
59. Naslund TI, Gehrmann U and Gabrielsson S. Cancer immunotherapy with exosomes requires B-cell activation. Oncoimmunology. 2013; 2:e24533.
60. Lee EY, Park KS, Yoon YJ, Lee J, Moon HG, Jang SC, Choi KH, Kim YK and Gho YS. Therapeutic effects of autologous tumor-derived nanovesicles on melanoma growth and metastasis. PloS One. 2012; 7:e33330.
61. Chaput N, Schartz NE, Andre F, Taieb J, Novault S, Bonnaventure P, Aubert N, Bernard J, Lemonnier F, Merad M, Adema G, Adams M, Ferrantini M, Carpentier AF, Escudier B, Tursz T, et al. Exosomes as potent cell-free peptide-based vaccine. II. Exosomes in CpG adjuvants efficiently prime naive Tc1 lymphocytes leading to tumor rejection. J Immunol. 2004; 172:2137-2146.
62. Hwu P, Shafer GE, Treisman J, Schindler DG, Gross G, Cowherd R, Rosenberg SA and Eshhar Z. Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain. J Exp Med. 1993; 178:361-366.
63. Hwu P, Yang JC, Cowherd R, Treisman J, Shafer GE, Eshhar Z and Rosenberg SA. in vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes. Cancer Res. 1995; 55:3369-3373.
64. Porter DL, Levine BL, Kalos M, Bagg A and June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011; 365:725-733.
65. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL and June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013; 368:1509-1518.
66. Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE, Raubitschek A, Forman SJ, Greenberg PD, Riddell SR and Press OW. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood. 2012; 119:3940-3950.
67. Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, Rossig C, Russell HV, Diouf O, Liu E, Liu H, Wu MF, Gee AP, Mei Z, Rooney CM, Heslop HE, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood. 2011; 118:6050-6056.
68. Brentjens RJ, Latouche JB, Santos E, Marti F, Gong MC, Lyddane C, King PD, Larson S, Weiss M, Riviere I and Sadelain M. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med. 2003; 9:279-286.
69. Sadelain M, Brentjens R and Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013; 3:388-398.
70. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015; 385:517-528.
71. Xu XJ and Tang YM. Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells. Cancer Lett. 2014; 343:172-178.
72. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012; 119:2709-2720.
73. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM and Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010; 18:843-851.
74. Brentjens R, Yeh R, Bernal Y, Riviere I and Sadelain M. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther . 2010; 18:666-668.
75. Maher J, Brentjens RJ, Gunset G, Riviere I and Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol. 2002; 20:70-75.
76. Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011; 365:1673-1683.
77. Lupo-Stanghellini MT, Provasi E, Bondanza A, Ciceri F, Bordignon C and Bonini C. Clinical impact of suicide gene therapy in allogeneic hematopoietic stem cell transplantation. Human Gene Ther. 2010; 21:241-250.
78. Peters PJ, Geuze HJ, Van der Donk HA, Slot JW, Griffith JM, Stam NJ, Clevers HC and Borst J. Molecules relevant for T cell-target cell interaction are present in cytolytic granules of human T lymphocytes. Eur J Immunol. 1989; 19:1469-1475.
79. Peters PJ, Borst J, Oorschot V, Fukuda M, Krahenbuhl O, Tschopp J, Slot JW and Geuze HJ. Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med. 1991; 173:1099-1109.
80. Peters PJ, Geuze HJ, van der Donk HA and Borst J. A new model for lethal hit delivery by cytotoxic T lymphocytes. Immunol Today. 1990; 11:28-32.
81. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z, Yvon E, Weiss HL, Liu H, Rooney CM, Heslop HE and Brenner MK. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008; 14:1264-1270.
82. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, Chen CC, Yang JC, Rosenberg SA and Hwu P. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006; 12:6106-6115.
83. Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer. 2005; 5:263-274.
84. Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, Ittmann MM, Marchetti D and Dotti G. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med. 2015; 21:524-529.
85. Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM, Barry FP, O'Brien T and Kerin MJ. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res. 2007; 13:5020-5027.
86. Dai LJ, Moniri MR, Zeng ZR, Zhou JX, Rayat J and Warnock GL. Potential implications of mesenchymal stem cells in cancer therapy. Cancer Lett. 2011; 305:8-20.
87. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S and Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011; 29:341-345.
88. Gyorgy B, Hung ME, Breakefield XO and Leonard JN. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu Rev Pharmacol Toxicol. 2015; 55:439-464.
89. Kidd S, Spaeth E, Dembinski JL, Dietrich M, Watson K, Klopp A, Battula VL, Weil M, Andreeff M and Marini FC. Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem cells. 2009; 27:2614-2623.
90. Ponte AL, Marais E, Gallay N, Langonne A, Delorme B, Herault O, Charbord P and Domenech J. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem cells. 2007; 25:1737-1745.
91. Kim HS, Choi DY, Yun SJ, Choi SM, Kang JW, Jung JW, Hwang D, Kim KP and Kim DW. Proteomic analysis of microvesicles derived from human mesenchymal stem cells. J Proteome Res. 2012; 11:839-849.
92. Markley JC and Sadelain M. IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice. Blood. 2010; 115:3508-3519.
93. Lippert TH, Ruoff HJ and Volm M. Current status of methods to assess cancer drug resistance. Int J Med Sci. 2011; 8:245-253.
94. Lippert TH, Ruoff HJ and Volm M. Intrinsic and acquired drug resistance in malignant tumors. The main reason for therapeutic failure. Arzneimittel-Forschung. 2008; 58:261-264.
95. Kochenderfer JN and Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013; 10:267-276.
96. Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, Gonzalez S, Sanchez-Cabo F, Gonzalez MA, Bernad A and Sanchez-Madrid F. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. 2011; 2:282.
97. Hao S, Bai O, Li F, Yuan J, Laferte S and Xiang J. Mature dendritic cells pulsed with exosomes stimulate efficient cytotoxic T-lymphocyte responses and antitumour immunity. Immunology. 2007; 120:90-102.
98. Sun XY, Nong J, Qin K, Lu H, Moniri MR, Dai LJ and Warnock GL. MSC(TRAIL)-mediated HepG2 cell death in direct and indirect co-cultures. Anticancer Res. 2011; 31:3705-3712.
99. Moniri MR, Sun XY, Rayat J, Dai D, Ao Z, He Z, Verchere CB, Dai LJ and Warnock GL. TRAIL-engineered pancreas-derived mesenchymal stem cells: characterization and cytotoxic effects on pancreatic cancer cells. Cancer Gene Ther. 2012; 19:652-658.
100. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS and Dzau VJ. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005; 11:367-368.
101. Lai RC, Yeo RW, Tan KH and Lim SK. Exosomes for drug delivery - a novel application for the mesenchymal stem cell. Biotechnol Adv. 2013; 31:543-551.
102. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D and Zhang HG. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010; 18:1606-1614.
103. Yang ZS, Tang XJ, Guo XR, Zou DD, Sun XY, Feng JB, Luo J, Dai LJ and Warnock GL. Cancer cell-oriented migration of mesenchymal stem cells engineered with an anticancer gene (PTEN): an imaging demonstration. OncoTargets Ther. 2014; 7:441-446.
104. Andre F, Chaput N, Schartz NE, Flament C, Aubert N, Bernard J, Lemonnier F, Raposo G, Escudier B, Hsu DH, Tursz T, Amigorena S, Angevin E and Zitvogel L. Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol. 2004; 172:2126-2136.
105. Cheruvanky A, Zhou H, Pisitkun T, Kopp JB, Knepper MA, Yuen PS and Star RA. Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. Am J Physiol Renal Physiol. 2007; 292:F1657-1661.
106. Lasser C, Eldh M and Lotvall J. Isolation and characterization of RNA-containing exosomes. J Vis Exp. 2012; :e3037.