Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Review Article

Cell vehicle targeting strategies

Abstract

Use of cells as therapeutic carriers has increased in the past few years and has developed as a distinct concept and delivery method. Cell-based vehicles are particularly attractive for delivery of biotherapeutic agents that are difficult to synthesize, have reduced half-lives, limited tissue penetrance or are rapidly inactivated upon direct in vivo introduction. Initial studies using cell-based approaches served to identify some of the key factors for the success of this type of therapeutic delivery. These factors include the efficiency of cell loading with a therapeutic payload, the means of cell loading and the nature of therapeutics that cells can carry. However, one important aspect of cell-based delivery yet to be fully investigated is the process of actual delivery of the cell payload in vivo. In this regard, the potential ability of cell carriers to provide site-specific or targeted delivery of therapeutics deserves special attention. The present review focuses on a variety of targeting approaches that may be utilized to improve cell-based therapeutic delivery strategies. The different aspects of targeting that can be applied to cell vehicles will be discussed, including physical methods for directing cell distribution, intrinsic cell-mediated homing mechanisms and the feasibility of engineering cells with novel targeting mechanisms. Development of cell targeting strategies will further advance cell vehicle applications, broaden the applicability of this delivery approach and potentiate therapeutic outcomes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Patel LN, Zaro JL, Shen WC . Cell penetrating peptides: intracellular pathways and pharmaceutical perspectives. Pharm Res 2007; 24: 1977–1992.

    Article  CAS  PubMed  Google Scholar 

  2. Vasir JK, Labhasetwar V . Biodegradable nanoparticles for cytosolic delivery of therapeutics. Adv Drug Deliv Rev 2007; 59: 718–728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yao SN, Smith KJ, Kurachi K . Primary myoblast-mediated gene transfer: persistent expression of human factor IX in mice. Gene Therapy 1994; 1: 99–107.

    CAS  PubMed  Google Scholar 

  4. Murphy JE, Rheinwald JG . Intraperitoneal injection of genetically modified, human mesothelial cells for systemic gene therapy. Hum Gene Ther 1997; 8: 1867–1879.

    Article  CAS  PubMed  Google Scholar 

  5. Naffakh N, Henri A, Villeval JL, Rouyer-Fessard P, Moullier P, Blumenfeld N et al. Sustained delivery of erythropoietin in mice by genetically modified skin fibroblasts. Proc Natl Acad Sci USA 1995; 92: 3194–3198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bachoud-Levi AC, Deglon N, Nguyen JP, Bloch J, Bourdet C, Winkel L et al. Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Hum Gene Ther 2000; 11: 1723–1729.

    Article  CAS  PubMed  Google Scholar 

  7. Ishida A, Yasuzumi F . Approach to ex vivo gene therapy in the treatment of Parkinson's disease. Brain Dev 2000; 22 (Suppl 1): S143–S147.

    Article  PubMed  Google Scholar 

  8. Conrad C, Gupta R, Mohan H, Niess H, Bruns CJ, Kopp R et al. Genetically engineered stem cells for therapeutic gene delivery. Curr Gene Ther 2007; 7: 249–260.

    Article  CAS  PubMed  Google Scholar 

  9. Reiser J, Zhang XY, Hemenway CS, Mondal D, Pradhan L, La Russa VF . Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases. Expert Opin Biol Ther 2005; 5: 1571–1584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cirone P, Bourgeois JM, Austin RC, Chang PL . A novel approach to tumor suppression with microencapsulated recombinant cells. Hum Gene Ther 2002; 13: 1157–1166.

    Article  CAS  PubMed  Google Scholar 

  11. Waehler R, Russell SJ, Curiel DT . Engineering targeted viral vectors for gene therapy. Nat Rev Genet 2007; 8: 573–587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li HJ, Everts M, Pereboeva L, Komarova S, Idan A, Curiel DT et al. Adenovirus tumor targeting and hepatic untargeting by a coxsackie/adenovirus receptor ectodomain anti-carcinoembryonic antigen bispecific adapter. Cancer Res 2007; 67: 5354–5361.

    Article  CAS  PubMed  Google Scholar 

  13. Kumar S, Ponnazhagan S . Bone homing of mesenchymal stem cells by ectopic alpha 4 integrin expression. FASEB J 2007; 21: 3917–3927.

    Article  CAS  PubMed  Google Scholar 

  14. Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN et al. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004; 96: 1593–1603.

    Article  CAS  PubMed  Google Scholar 

  15. Qiao J, Kottke T, Willmon C, Galivo F, Wongthida P, Diaz RM et al. Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy. Nat Med 2008; 14: 37–44.

    Article  CAS  PubMed  Google Scholar 

  16. Komarova S, Kawakami Y, Stoff-Khalili MA, Curiel DT, Pereboeva L . Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses. Mol Cancer Ther 2006; 5: 755–766.

    Article  CAS  PubMed  Google Scholar 

  17. Thorne SH, Negrin RS, Contag CH . Synergistic antitumor effects of immune cell-viral biotherapy. Science 2006; 311: 1780–1784.

    Article  CAS  PubMed  Google Scholar 

  18. Chester J, Ruchatz A, Gough M, Crittenden M, Chong H, Cosset FL et al. Tumor antigen-specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor-modified T cells. Nat Biotechnol 2002; 20: 256–263.

    Article  CAS  PubMed  Google Scholar 

  19. Sanz L, Qiao J, Vile RG, Alvarez-Vallina L . Antibody engineering, virus retargeting and cellular immunotherapy: one ring to rule them all? Curr Gene Ther 2005; 5: 63–70.

    Article  CAS  PubMed  Google Scholar 

  20. Al Kindi A, Ge Y, Shum-Tim D, Chiu RC . Cellular cardiomyoplasty: routes of cell delivery and retention. Front Biosci 2008; 13: 2421–2434.

    Article  CAS  PubMed  Google Scholar 

  21. Kawabata K, Migita M, Mochizuki H, Miyake K, Igarashi T, Fukunaga Y et al. Ex vivo cell-mediated gene therapy for metachromatic leukodystrophy using neurospheres. Brain Res 2006; 1094: 13–23.

    Article  CAS  PubMed  Google Scholar 

  22. Parr AM, Kulbatski I, Tator CH . Transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury. J Neurotrauma 2007; 24: 835–845.

    Article  PubMed  Google Scholar 

  23. Poh KK, Sperry E, Young RG, Freyman T, Barringhaus KG, Thompson CA . Repeated direct endomyocardial transplantation of allogeneic mesenchymal stem cells: safety of a high dose, ‘off-the-shelf’, cellular cardiomyoplasty strategy. Int J Cardiol 2007; 117: 360–364.

    Article  PubMed  Google Scholar 

  24. Mi Q, Riviere B, Clermont G, Steed DL, Vodovotz Y . Agent-based model of inflammation and wound healing: insights into diabetic foot ulcer pathology and the role of transforming growth factor-beta1. Wound Repair Regen 2007; 15: 671–682.

    Article  PubMed  Google Scholar 

  25. Dick AJ, Guttman MA, Raman VK, Peters DC, Pessanha BS, Hill JM et al. Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in swine. Circulation 2003; 108: 2899–2904.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sprandel U, Lanz DJ, von Horsten W . Magnetically responsive erythrocyte ghosts. Methods Enzymol 1987; 149: 301–312.

    Article  CAS  PubMed  Google Scholar 

  27. Daldrup-Link HE, Meier R, Rudelius M, Piontek G, Piert M, Metz S et al. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging. Eur Radiol 2005; 15: 4–13.

    Article  PubMed  Google Scholar 

  28. Daldrup-Link HE, Rudelius M, Piontek G, Metz S, Brauer R, Debus G et al. Migration of iron oxide-labeled human hematopoietic progenitor cells in a mouse model: in vivo monitoring with 1.5-T MR imaging equipment. Radiology 2005; 234: 197–205.

    Article  PubMed  Google Scholar 

  29. Hauger O, Frost EE, van Heeswijk R, Deminiere C, Xue R, Delmas Y et al. MR evaluation of the glomerular homing of magnetically labeled mesenchymal stem cells in a rat model of nephropathy. Radiology 2006; 238: 200–210.

    Article  PubMed  Google Scholar 

  30. Nakashima Y, Deie M, Yanada S, Sharman P, Ochi M . Magnetically labeled human natural killer cells, accumulated in vitro by an external magnetic force, are effective against HOS osteosarcoma cells. Int J Oncol 2005; 27: 965–971.

    CAS  PubMed  Google Scholar 

  31. Arbab AS, Jordan EK, Wilson LB, Yocum GT, Lewis BK, Frank JA . In vivo trafficking and targeted delivery of magnetically labeled stem cells. Hum Gene Ther 2004; 15: 351–360.

    Article  CAS  PubMed  Google Scholar 

  32. Polyak B, Fishbein I, Chorny M, Alferiev I, Williams D, Yellen B et al. High field gradient targeting of magnetic nanoparticle-loaded endothelial cells to the surfaces of steel stents. Proc Natl Acad Sci USA 2008; 105: 698–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pierige F, Serafini S, Rossi L, Magnani M . Cell-based drug delivery. Adv Drug Deliv Rev 2008; 60: 286–295.

    Article  CAS  PubMed  Google Scholar 

  34. Rossi L, Serafini S, Pierige F, Castro M, Ambrosini MI, Knafelz D et al. Erythrocytes as a controlled drug delivery system: clinical evidences. J Control Release 2006; 116: e43–e45.

    Article  CAS  PubMed  Google Scholar 

  35. Rossi L, Serafini S, Pierige F, Antonelli A, Cerasi A, Fraternale A et al. Erythrocyte-based drug delivery. Expert Opin Drug Deliv 2005; 2: 311–322.

    Article  CAS  PubMed  Google Scholar 

  36. Rossi L, Franchetti P, Pierige F, Cappellacci L, Serafini S, Balestra E et al. Inhibition of HIV-1 replication in macrophages by a heterodinucleotide of lamivudine and tenofovir. J Antimicrob Chemother 2007; 59: 666–675.

    Article  CAS  PubMed  Google Scholar 

  37. Mishra PR, Jain NK . Surface modified methotrexate loaded erythrocytes for enhanced macrophage uptake. J Drug Target 2000; 8: 217–224.

    Article  CAS  PubMed  Google Scholar 

  38. Hamidi M, Zarrin A, Foroozesh M, Mohammadi-Samani S . Applications of carrier erythrocytes in delivery of biopharmaceuticals. J Control Release 2007; 118: 145–160.

    Article  CAS  PubMed  Google Scholar 

  39. Stoff-Khalili MA, Rivera AA, Mathis JM, Banerjee NS, Moon AS, Hess A et al. Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma. Breast Cancer Res Treat 2007; 105: 157–167.

    Article  PubMed  Google Scholar 

  40. Hakkarainen T, Sarkioja M, Lehenkari P, Miettinen S, Ylikomi T, Suuronen R et al. Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors. Hum Gene Ther 2007; 18: 627–641.

    Article  CAS  PubMed  Google Scholar 

  41. Melder RJ, Kristensen CA, Munn LL, Jain RK . Modulation of A-NK cell rigidity: in vitro characterization and in vivo implications for cell delivery. Biorheology 2001; 38: 151–159.

    CAS  PubMed  Google Scholar 

  42. Kuppen PJ, Marinelli A, Camps JA, Pauwels EK, van de Velde CJ, Fleuren GJ et al. Biodistribution of lymphokine-activated killer (LAK) cells in Wag rats after hepatic-artery or jugular-vein infusion. Int J Cancer 1992; 52: 266–270.

    Article  CAS  PubMed  Google Scholar 

  43. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI . The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001; 169: 12–20.

    Article  CAS  PubMed  Google Scholar 

  44. Muller WA . Leukocyte–endothelial cell interactions in the inflammatory response. Lab Invest 2002; 82: 521–533.

    Article  CAS  PubMed  Google Scholar 

  45. Foxall C, Watson SR, Dowbenko D, Fennie C, Lasky LA, Kiso M et al. The three members of the selectin receptor family recognize a common carbohydrate epitope, the sialyl Lewis(x) oligosaccharide. J Cell Biol 1992; 117: 895–902.

    Article  CAS  PubMed  Google Scholar 

  46. Lawrence MB, Springer TA . Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell 1991; 65: 859–873.

    Article  CAS  PubMed  Google Scholar 

  47. Olson TS, Ley K . Chemokines and chemokine receptors in leukocyte trafficking. Am J Physiol Regul Integr Comp Physiol 2002; 283: R7–28.

    Article  CAS  PubMed  Google Scholar 

  48. Le Y, Zhou Y, Iribarren P, Wang J . Chemokines and chemokine receptors: their manifold roles in homeostasis and disease. Cell Mol Immunol 2004; 1: 95–104.

    CAS  PubMed  Google Scholar 

  49. Dustin ML, Springer TA . Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecule-1 (ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol 1988; 107: 321–331.

    Article  CAS  PubMed  Google Scholar 

  50. Haskard D, Cavender D, Beatty P, Springer T, Ziff M . T lymphocyte adhesion to endothelial cells: mechanisms demonstrated by anti-LFA-1 monoclonal antibodies. J Immunol 1986; 137: 2901–2906.

    CAS  PubMed  Google Scholar 

  51. von Andrian UH, Mackay CR . T-cell function and migration. Two sides of the same coin. N Engl J Med 2000; 343: 1020–1034.

    Article  CAS  PubMed  Google Scholar 

  52. Stein JV, Nombela-Arrieta C . Chemokine control of lymphocyte trafficking: a general overview. Immunology 2005; 116: 1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mora JR, von Andrian UH . T-cell homing specificity and plasticity: new concepts and future challenges. Trends Immunol 2006; 27: 235–243.

    Article  CAS  PubMed  Google Scholar 

  54. Tanaka T, Ebisuno Y, Kanemitsu N, Umemoto E, Yang BG, Jang MH et al. Molecular determinants controlling homeostatic recirculation and tissue-specific trafficking of lymphocytes. Int Arch Allergy Immunol 2004; 134: 120–134.

    Article  PubMed  Google Scholar 

  55. Dudley ME, Rosenberg SA . Adoptive cell transfer therapy. Semin Oncol 2007; 34: 524–531.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Dudley ME, Rosenberg SA . Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 2003; 3: 666–675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mukai S, Kjaergaard J, Shu S, Plautz GE . Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy. Cancer Res 1999; 59: 5245–5249.

    CAS  PubMed  Google Scholar 

  58. Brown CE, Vishwanath RP, Aguilar B, Starr R, Najbauer J, Aboody KS et al. Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells. J Immunol 2007; 179: 3332–3341.

    Article  CAS  PubMed  Google Scholar 

  59. Gu L, Tseng S, Horner RM, Tam C, Loda M, Rollins BJ . Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 2000; 404: 407–411.

    Article  CAS  PubMed  Google Scholar 

  60. Goerdt S, Orfanos CE . Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 1999; 10: 137–142.

    Article  CAS  PubMed  Google Scholar 

  61. Zhang T, Somasundaram R, Berking C, Caputo L, Van Belle P, Elder D et al. Preferential involvement of CX chemokine receptor 4 and CX chemokine ligand 12 in T-cell migration toward melanoma cells. Cancer Biol Ther 2006; 5: 1304–1312.

    Article  CAS  PubMed  Google Scholar 

  62. Thanarajasingam U, Sanz L, Diaz R, Qiao J, Sanchez-Perez L, Kottke T et al. Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy. Cancer Res 2007; 67: 300–308.

    Article  CAS  PubMed  Google Scholar 

  63. Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D, Balint K et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med 2008; 14: 28–36.

    Article  CAS  PubMed  Google Scholar 

  64. Bernhard H, Neudorfer J, Gebhard K, Conrad H, Hermann C, Nahrig J et al. Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer. Cancer Immunol Immunother 2008; 57: 271–280.

    Article  PubMed  Google Scholar 

  65. Marshall NA, Christie LE, Munro LR, Culligan DJ, Johnston PW, Barker RN et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 2004; 103: 1755–1762.

    Article  CAS  PubMed  Google Scholar 

  66. Niehans GA, Brunner T, Frizelle SP, Liston JC, Salerno CT, Knapp DJ et al. Human lung carcinomas express Fas ligand. Cancer Res 1997; 57: 1007–1012.

    CAS  PubMed  Google Scholar 

  67. Cole C, Qiao J, Kottke T, Diaz RM, Ahmed A, Sanchez-Perez L et al. Tumor-targeted, systemic delivery of therapeutic viral vectors using hitchhiking on antigen-specific T cells. Nat Med 2005; 11: 1073–1081.

    Article  CAS  PubMed  Google Scholar 

  68. Crittenden M, Gough M, Chester J, Kottke T, Thompson J, Ruchatz A et al. Pharmacologically regulated production of targeted retrovirus from T cells for systemic antitumor gene therapy. Cancer Res 2003; 63: 3173–3180.

    CAS  PubMed  Google Scholar 

  69. Ong HT, Hasegawa K, Dietz AB, Russell SJ, Peng KW . Evaluation of T cells as carriers for systemic measles virotherapy in the presence of antiviral antibodies. Gene Therapy 2007; 14: 324–333.

    Article  CAS  PubMed  Google Scholar 

  70. Harrington K, Alvarez-Vallina L, Crittenden M, Gough M, Chong H, Diaz RM et al. Cells as vehicles for cancer gene therapy: the missing link between targeted vectors and systemic delivery? Hum Gene Ther 2002; 13: 1263–1280.

    Article  CAS  PubMed  Google Scholar 

  71. Boxio R, Bossenmeyer-Pourie C, Steinckwich N, Dournon C, Nusse O . Mouse bone marrow contains large numbers of functionally competent neutrophils. J Leukoc Biol 2004; 75: 604–611.

    Article  CAS  PubMed  Google Scholar 

  72. Henson PM, Johnston Jr RB . Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J Clin Invest 1987; 79: 669–674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Weiss SJ . Tissue destruction by neutrophils. N Engl J Med 1989; 320: 365–376.

    Article  CAS  PubMed  Google Scholar 

  74. Savill JS, Wyllie AH, Henson JE, Walport MJ, Henson PM, Haslett C . Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. J Clin Invest 1989; 83: 865–875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hand WL, Hand DL . Characteristics and mechanisms of azithromycin accumulation and efflux in human polymorphonuclear leukocytes. Int J Antimicrob Agents 2001; 18: 419–425.

    Article  CAS  PubMed  Google Scholar 

  76. Suratt BT, Young SK, Lieber J, Nick JA, Henson PM, Worthen GS . Neutrophil maturation and activation determine anatomic site of clearance from circulation. Am J Physiol Lung Cell Mol Physiol 2001; 281: L913–L921.

    Article  CAS  PubMed  Google Scholar 

  77. Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 2006; 311: 83–87.

    Article  CAS  PubMed  Google Scholar 

  78. Geissmann F, Jung S, Littman DR . Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003; 19: 71–82.

    Article  CAS  PubMed  Google Scholar 

  79. Libby P . Inflammation in atherosclerosis. Nature 2002; 420: 868–874.

    Article  CAS  PubMed  Google Scholar 

  80. Mack M, Bruhl H, Gruber R, Jaeger C, Cihak J, Eiter V et al. Predominance of mononuclear cells expressing the chemokine receptor CCR5 in synovial effusions of patients with different forms of arthritis. Arthritis Rheum 1999; 42: 981–988.

    Article  CAS  PubMed  Google Scholar 

  81. Liang CP, Han S, Senokuchi T, Tall AR . The macrophage at the crossroads of insulin resistance and atherosclerosis. Circ Res 2007; 100: 1546–1555.

    Article  CAS  PubMed  Google Scholar 

  82. O'Sullivan C, Lewis CE . Tumour-associated leucocytes: friends or foes in breast carcinoma. J Pathol 1994; 172: 229–235.

    Article  CAS  PubMed  Google Scholar 

  83. Bingle L, Brown NJ, Lewis CE . The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 2002; 196: 254–265.

    Article  CAS  PubMed  Google Scholar 

  84. Wiltrout RH, Brunda MJ, Gorelik E, Peterson ES, Dunn JJ, Leonhardt J et al. Distribution of peritoneal macrophage populations after intravenous injection in mice: differential effects of eliciting and activating agents. J Reticuloendothel Soc 1983; 34: 253–269.

    CAS  PubMed  Google Scholar 

  85. Lesimple T, Moisan A, Toujas L . Autologous human macrophages and anti-tumour cell therapy. Res Immunol 1998; 149: 663–671.

    Article  CAS  PubMed  Google Scholar 

  86. Audran R, Collet B, Moisan A, Toujas L . Fate of mouse macrophages radiolabelled with PKH-95 and injected intravenously. Nucl Med Biol 1995; 22: 817–821.

    Article  CAS  PubMed  Google Scholar 

  87. Rosen H, Gordon S . Adoptive transfer of fluorescence-labeled cells shows that resident peritoneal macrophages are able to migrate into specialized lymphoid organs and inflammatory sites in the mouse. Eur J Immunol 1990; 20: 1251–1258.

    Article  CAS  PubMed  Google Scholar 

  88. Unsgaard G, Hammerstrom J, Lamvik J . Cytostatic effect on tumour cells induced in human monocytes by mediators from BCG-stimulated lymphocytes and MLC. Acta Pathol Microbiol Scand (C) 1979; 87C: 159–166.

    CAS  Google Scholar 

  89. Kircher MF, Grimm J, Swirski FK, Libby P, Gerszten RE, Allport JR et al. Noninvasive in vivo imaging of monocyte trafficking to atherosclerotic lesions. Circulation 2008; 117: 388–395.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Jin H, Su J, Garmy-Susini B, Kleeman J, Varner J . Integrin alpha4beta1 promotes monocyte trafficking and angiogenesis in tumors. Cancer Res 2006; 66: 2146–2152.

    Article  CAS  PubMed  Google Scholar 

  91. Tacke F, Randolph GJ . Migratory fate and differentiation of blood monocyte subsets. Immunobiology 2006; 211: 609–618.

    Article  CAS  PubMed  Google Scholar 

  92. Imhof BA, Aurrand-Lions M . Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol 2004; 4: 432–444.

    Article  CAS  PubMed  Google Scholar 

  93. Dragomir E, Simionescu M . Monocyte chemoattractant protein-1—a major contributor to the inflammatory process associated with diabetes. Arch Physiol Biochem 2006; 112: 239–244.

    Article  CAS  PubMed  Google Scholar 

  94. Mahad DJ, Ransohoff RM . The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Semin Immunol 2003; 15: 23–32.

    Article  CAS  PubMed  Google Scholar 

  95. Marra F . Renaming cytokines: MCP-1, major chemokine in pancreatitis. Gut 2005; 54: 1679–1681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Charo IF, Taubman MB . Chemokines in the pathogenesis of vascular disease. Circ Res 2004; 95: 858–866.

    Article  CAS  PubMed  Google Scholar 

  97. Wright DE, Bowman EP, Wagers AJ, Butcher EC, Weissman IL . Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J Exp Med 2002; 195: 1145–1154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004; 10: 858–864.

    Article  CAS  PubMed  Google Scholar 

  99. Hitchon C, Wong K, Ma G, Reed J, Lyttle D, El-Gabalawy H . Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum 2002; 46: 2587–2597.

    Article  CAS  PubMed  Google Scholar 

  100. Zlotnik A . Chemokines in neoplastic progression. Semin Cancer Biol 2004; 14: 181–185.

    Article  CAS  PubMed  Google Scholar 

  101. Spring H, Schuler T, Arnold B, Hammerling GJ, Ganss R . Chemokines direct endothelial progenitors into tumor neovessels. Proc Natl Acad Sci USA 2005; 102: 18111–18116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Klopp AH, Spaeth EL, Dembinski JL, Woodward WA, Munshi A, Meyn RE et al. Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res 2007; 67: 11687–11695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res 2007; 13: 5020–5027.

    Article  CAS  PubMed  Google Scholar 

  104. Misao Y, Takemura G, Arai M, Ohno T, Onogi H, Takahashi T et al. Importance of recruitment of bone marrow-derived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF. Cardiovasc Res 2006; 71: 455–465.

    Article  CAS  PubMed  Google Scholar 

  105. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001; 98: 10344–10349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Liu J, Harada H, Ogura M, Shibata T, Hiraoka M . Adenovirus-mediated hypoxia-targeting cytosine deaminase gene therapy enhances radiotherapy in tumour xenografts. Br J Cancer 2007; 96: 1871–1878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kizaka-Kondoh S, Inoue M, Harada H, Hiraoka M . Tumor hypoxia: a target for selective cancer therapy. Cancer Sci 2003; 94: 1021–1028.

    Article  CAS  PubMed  Google Scholar 

  108. Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 2002; 3: 687–694.

    Article  CAS  PubMed  Google Scholar 

  109. Link DC . Mechanisms of granulocyte colony-stimulating factor-induced hematopoietic progenitor-cell mobilization. Semin Hematol 2000; 37: 25–32.

    Article  CAS  PubMed  Google Scholar 

  110. Liles WC, Broxmeyer HE, Rodger E, Wood B, Hubel K, Cooper S et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 2003; 102: 2728–2730.

    Article  CAS  PubMed  Google Scholar 

  111. Zohlnhofer D, Kastrati A, Schomig A . Stem cell mobilization by granulocyte-colony-stimulating factor in acute myocardial infarction: lessons from the REVIVAL-2 trial. Nat Clin Pract Cardiovasc Med 2007; 4 (Suppl 1): S106–S109.

    Article  PubMed  CAS  Google Scholar 

  112. de Bont ES, Guikema JE, Scherpen F, Meeuwsen T, Kamps WA, Vellenga E et al. Mobilized human CD34+ hematopoietic stem cells enhance tumor growth in a nonobese diabetic/severe combined immunodeficient mouse model of human non-Hodgkin's lymphoma. Cancer Res 2001; 61: 7654–7659.

    CAS  PubMed  Google Scholar 

  113. Ramasamy R, Lam EW, Soeiro I, Tisato V, Bonnet D, Dazzi F et al. Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia 2007; 21: 304–310.

    Article  CAS  PubMed  Google Scholar 

  114. Blau CA, Peterson KR, Drachman JG, Spencer DM . A proliferation switch for genetically modified cells. Proc Natl Acad Sci USA 1997; 94: 3076–3081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sauvageau G, Iscove NN, Humphries RK . In vitro and in vivo expansion of hematopoietic stem cells. Oncogene 2004; 23: 7223–7232.

    Article  CAS  PubMed  Google Scholar 

  116. Richard RE, Wood B, Zeng H, Jin L, Papayannopoulou T, Blau CA . Expansion of genetically modified primary human hemopoietic cells using chemical inducers of dimerization. Blood 2000; 95: 430–436.

    CAS  PubMed  Google Scholar 

  117. Vollweiler JL, Zielske SP, Reese JS, Gerson SL . Hematopoietic stem cell gene therapy: progress toward therapeutic targets. Bone Marrow Transplant 2003; 32: 1–7.

    Article  CAS  PubMed  Google Scholar 

  118. Davis BM, Koc ON, Gerson SL . Limiting numbers of G156A O(6)-methylguanine-DNA methyltransferase-transduced marrow progenitors repopulate nonmyeloablated mice after drug selection. Blood 2000; 95: 3078–3084.

    CAS  PubMed  Google Scholar 

  119. Li W, Ma N, Ong LL, Nesselmann C, Klopsch C, Ladilov Y et al. Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells 2007; 25: 2118–2127.

    Article  CAS  PubMed  Google Scholar 

  120. Charo J, Finkelstein SE, Grewal N, Restifo NP, Robbins PF, Rosenberg SA . Bcl-2 overexpression enhances tumor-specific T-cell survival. Cancer Res 2005; 65: 2001–2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhao H, Yenari MA, Cheng D, Sapolsky RM, Steinberg GK . Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. J Neurochem 2003; 85: 1026–1036.

    Article  CAS  PubMed  Google Scholar 

  122. Chen Z, Chua CC, Ho YS, Hamdy RC, Chua BH . Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol 2001; 280: H2313–H2320.

    Article  CAS  PubMed  Google Scholar 

  123. Huang G, Zheng Q, Sun J, Guo C, Yang J, Chen R et al. Stabilization of cellular properties and differentiation multipotential of human mesenchymal stem cells transduced with hTERT gene in a long-term culture. J Cell Biochem 2007; 103: 1256–1269.

    Article  CAS  Google Scholar 

  124. Huang Q, Chen M, Liang S, Acha V, Liu D, Yuan F et al. Improving cell therapy—experiments using transplanted telomerase-immortalized cells in immunodeficient mice. Mech Ageing Dev 2007; 128: 25–30.

    Article  CAS  PubMed  Google Scholar 

  125. Dmitriev I, Krasnykh V, Miller CR, Wang M, Kashentseva E, Mikheeva G et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J Virol 1998; 72: 9706–9713.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Peng KW, Donovan KA, Schneider U, Cattaneo R, Lust JA, Russell SJ . Oncolytic measles viruses displaying a single-chain antibody against CD38, a myeloma cell marker. Blood 2003; 101: 2557–2562.

    Article  CAS  PubMed  Google Scholar 

  127. Hasegawa K, Nakamura T, Harvey M, Ikeda Y, Oberg A, Figini M et al. The use of a tropism-modified measles virus in folate receptor-targeted virotherapy of ovarian cancer. Clin Cancer Res 2006; 12: 6170–6178.

    Article  CAS  PubMed  Google Scholar 

  128. Peng KW, Holler PD, Orr BA, Kranz DM, Russell SJ . Targeting virus entry and membrane fusion through specific peptide/MHC complexes using a high-affinity T-cell receptor. Gene Therapy 2004; 11: 1234–1239.

    Article  CAS  PubMed  Google Scholar 

  129. Belousova N, Mikheeva G, Gelovani J, Krasnykh V . Modification of adenovirus capsid with a designed protein ligand yields a gene vector targeted to a major molecular marker of cancer. J Virol 2008; 82: 630–637.

    Article  CAS  PubMed  Google Scholar 

  130. Haisma HJ, Grill J, Curiel DT, Hoogeland S, van Beusechem VW, Pinedo HM et al. Targeting of adenoviral vectors through a bispecific single-chain antibody. Cancer Gene Ther 2000; 7: 901–904.

    Article  CAS  PubMed  Google Scholar 

  131. Sebestyen Z, de Vrij J, Magnusson M, Debets R, Willemsen R . An oncolytic adenovirus redirected with a tumor-specific T-cell receptor. Cancer Res 2007; 67: 11309–11316.

    Article  CAS  PubMed  Google Scholar 

  132. Alvarez-Vallina L . Genetic approaches for antigen-selective cell therapy. Curr Gene Ther 2001; 1: 385–397.

    Article  CAS  PubMed  Google Scholar 

  133. Willemsen RA, Debets R, Chames P, Bolhuis RL . Genetic engineering of T cell specificity for immunotherapy of cancer. Hum Immunol 2003; 64: 56–68.

    Article  CAS  PubMed  Google Scholar 

  134. Brentjens RJ, Santos E, Nikhamin Y, Yeh R, Matsushita M, La Perle K et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res 2007; 13: 5426–5435.

    Article  CAS  PubMed  Google Scholar 

  135. Stephan MT, Ponomarev V, Brentjens RJ, Chang AH, Dobrenkov KV, Heller G et al. T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med 2007; 13: 1440–1449.

    Article  CAS  PubMed  Google Scholar 

  136. Jensen MC, Cooper LJ, Wu AM, Forman SJ, Raubitschek A . Engineered CD20-specific primary human cytotoxic T lymphocytes for targeting B-cell malignancy. Cytotherapy 2003; 5: 131–138.

    Article  CAS  PubMed  Google Scholar 

  137. Hombach A, Muche JM, Gerken M, Gellrich S, Heuser C, Pohl C et al. T cells engrafted with a recombinant anti-CD30 receptor target autologous CD30(+) cutaneous lymphoma cells. Gene Therapy 2001; 8: 891–895.

    Article  CAS  PubMed  Google Scholar 

  138. Cooper LJ, Topp MS, Serrano LM, Gonzalez S, Chang WC, Naranjo A et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood 2003; 101: 1637–1644.

    Article  CAS  PubMed  Google Scholar 

  139. Gade TP, Hassen W, Santos E, Gunset G, Saudemont A, Gong MC et al. Targeted elimination of prostate cancer by genetically directed human T lymphocytes. Cancer Res 2005; 65: 9080–9088.

    Article  CAS  PubMed  Google Scholar 

  140. June CH . Adoptive T cell therapy for cancer in the clinic. J Clin Invest 2007; 117: 1466–1476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ravetch JV . Fc receptors. Curr Opin Immunol 1997; 9: 121–125.

    Article  CAS  PubMed  Google Scholar 

  142. Morton HC, van Egmond M, van de Winkel JG . Structure and function of human IgA Fc receptors (Fc alpha R). Crit Rev Immunol 1996; 16: 423–440.

    CAS  PubMed  Google Scholar 

  143. Stockmeyer B, Dechant M, van Egmond M, Tutt AL, Sundarapandiyan K, Graziano RF et al. Triggering Fc alpha-receptor I (CD89) recruits neutrophils as effector cells for CD20-directed antibody therapy. J Immunol 2000; 165: 5954–5961.

    Article  CAS  PubMed  Google Scholar 

  144. Blanco B, Holliger P, Vile RG, Alvarez-Vallina L . Induction of human T lymphocyte cytotoxicity and inhibition of tumor growth by tumor-specific diabody-based molecules secreted from gene-modified bystander cells. J Immunol 2003; 171: 1070–1077.

    Article  CAS  PubMed  Google Scholar 

  145. Compte M, Blanco B, Serrano F, Cuesta AM, Sanz L, Bernad A et al. Inhibition of tumor growth in vivo by in situ secretion of bispecific anti-CEA x anti-CD3 diabodies from lentivirally transduced human lymphocytes. Cancer Gene Ther 2007; 14: 380–388.

    Article  CAS  PubMed  Google Scholar 

  146. Chan JK, Hamilton CA, Cheung MK, Karimi M, Baker J, Gall JM et al. Enhanced killing of primary ovarian cancer by retargeting autologous cytokine-induced killer cells with bispecific antibodies: a preclinical study. Clin Cancer Res 2006; 12: 1859–1867.

    Article  CAS  PubMed  Google Scholar 

  147. Chesnut JD, Baytan AR, Russell M, Chang MP, Bernard A, Maxwell IH et al. Selective isolation of transiently transfected cells from a mammalian cell population with vectors expressing a membrane anchored single-chain antibody. J Immunol Methods 1996; 193: 17–27.

    Article  CAS  PubMed  Google Scholar 

  148. Biglari A, Southgate TD, Fairbairn LJ, Gilham DE . Human monocytes expressing a CEA-specific chimeric CD64 receptor specifically target CEA-expressing tumour cells in vitro and in vivo. Gene Therapy 2006; 13: 602–610.

    Article  CAS  PubMed  Google Scholar 

  149. Hamdy N, Goustin AS, Desaulniers JP, Li M, Chow CS, Al-Katib A . Sheep red blood cells armed with anti-CD20 single-chain variable fragments (scFvs) fused to a glycosylphosphatidylinositol (GPI) anchor: a strategy to target CD20-positive tumor cells. J Immunol Methods 2005; 297: 109–124.

    Article  CAS  PubMed  Google Scholar 

  150. Douglas JT, Miller CR, Kim M, Dmitriev I, Mikheeva G, Krasnykh V et al. A system for the propagation of adenoviral vectors with genetically modified receptor specificities. Nat Biotechnol 1999; 17: 470–475.

    Article  CAS  PubMed  Google Scholar 

  151. Suzuki M, Shinkai M, Honda H, Kamihira M, Iijima S, Kobayashi T . Construction of tumor-specific cells expressing a membrane-anchored single-chain Fv of anti-ErbB-2 antibody. Biochim Biophys Acta 2001; 1525: 191–196.

    Article  CAS  PubMed  Google Scholar 

  152. Sharkey RM, McBride WJ, Karacay H, Chang K, Griffiths GL, Hansen HJ et al. A universal pretargeting system for cancer detection and therapy using bispecific antibody. Cancer Res 2003; 63: 354–363.

    CAS  PubMed  Google Scholar 

  153. Gough M, Crittenden M, Thanarajasingam U, Sanchez-Perez L, Thompson J, Jevremovic D et al. Gene therapy to manipulate effector T cell trafficking to tumors for immunotherapy. J Immunol 2005; 174: 5766–5773.

    Article  CAS  PubMed  Google Scholar 

  154. Wu J, Yang S, Luo H, Zeng L, Ye L, Lu Y . Quantitative evaluation of monocyte transmigration into the brain following chemical opening of the blood–brain barrier in mice. Brain Res 2006; 1098: 79–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Hammerberg C, Duraiswamy N, Cooper KD . Temporal correlation between UV radiation locally-inducible tolerance and the sequential appearance of dermal, then epidermal, class II MHC+CD11b+ monocytic/macrophagic cells. J Invest Dermatol 1996; 107: 755–763.

    Article  CAS  PubMed  Google Scholar 

  156. Zhang AY, Wu C, Zhou L, Ismail SA, Tao J, McCormick LL et al. Transduced monocyte/macrophages targeted to murine skin by UV light. Exp Dermatol 2006; 15: 51–57.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants 1 R21 CA115568 (to Dr L Pereboeva), T32 CA075930-08 and 5R01CA083821-08 (to Dr DT Curiel).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to J C Roth or L Pereboeva.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roth, J., Curiel, D. & Pereboeva, L. Cell vehicle targeting strategies. Gene Ther 15, 716–729 (2008). https://doi.org/10.1038/gt.2008.38

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2008.38

Keywords

This article is cited by

Search

Quick links