Immunotherapy of Cancer pp 319-345

Part of the Methods in Molecular Biology book series (MIMB, volume 651)

Cellular Immunotherapy of Cancer

  • Fatma V. Okur
  • Malcolm K. Brenner


Standard therapies for many common cancers remain toxic and are often ineffective. Cellular immunotherapy has the potential to be a highly targeted alternative, with low toxicity to normal tissues but a high capacity to eradicate tumor. In this chapter we describe approaches that generate cellular therapies using active immunization with cells, proteins, peptides, or nucleic acids, as well as efforts that use adoptive transfer of effector cells that directly target antigens on malignant cells. Many of these approaches are proving successful in hematologic malignancy and in melanoma. In this chapter we discuss the advantages and limitations of each and how over the next decade investigators will attempt to broaden their reach, increase their efficacy, and simplify their application.

Key words

Cancer immunotherapy tumor vaccines adoptive cell therapy and T cells 


  1. 1.
    Kim, E. S., Vokes, E. E., and Kies, M. S. (2004) Cetuximab in cancers of the lung and head & neck. Semin Oncol 31, 61–67.PubMedCrossRefGoogle Scholar
  2. 2.
    Mendelsohn, J. (1997) Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy. Clin Cancer Res 3, 2703–2707.PubMedGoogle Scholar
  3. 3.
    Piccart-Gebhart, M. J., Procter, M., Leyland-Jones, B., Goldhirsch, A., Untch, M., Smith, I., Gianni, L., Baselga, J., Bell, R., Jackisch, C., Cameron, D., Dowsett, M., Barrios, C. H., Steger, G., Huang, C. S., Andersson, M., Inbar, M., Lichinitser, M., Lang, I., Nitz, U., Iwata, H., Thomssen, C., Lohrisch, C., Suter, T. M., Ruschoff, J., Suto, T., Greatorex, V., Ward, C., Straehle, C., McFadden, E., Dolci, M. S., and Gelber, R. D. (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353, 1659–1672.PubMedCrossRefGoogle Scholar
  4. 4.
    Weiner, G. J., and Link, B. K. (2004) Monoclonal antibody therapy of B cell lymphoma. Expert Opin Biol Ther 4, 375–385.PubMedCrossRefGoogle Scholar
  5. 5.
    Giaccone, G. (2005) Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 23, 3235–3242.PubMedCrossRefGoogle Scholar
  6. 6.
    Graziano, D. F., and Finn, O. J. (2005) Tumor antigens and tumor antigen discovery. Cancer Treat Res 123, 89–111.PubMedCrossRefGoogle Scholar
  7. 7.
    Renkvist, N., Castelli, C., Robbins, P. F., and Parmiani, G. (2001) A listing of human tumor antigens recognized by T cells. Cancer Immunol Immunother 50, 3–15.PubMedCrossRefGoogle Scholar
  8. 8.
    Van Der Bruggen, P., Zhang, Y., Chaux, P., Stroobant, V., Panichelli, C., Schultz, E. S., Chapiro, J., Van Den Eynde, B. J., Brasseur, F., and Boon, T. (2002) Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev 188, 51–64.CrossRefGoogle Scholar
  9. 9.
    Drake, C. G., Jaffee, E., and Pardoll, D. M. (2006) Mechanisms of immune evasion by tumors. Adv Immunol 90, 51–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Smyth, M. J., Godfrey, D. I., and Trapani, J. A. (2001) A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2, 293–299.PubMedCrossRefGoogle Scholar
  11. 11.
    Cho, H. J., Takabayashi, K., Cheng, P. M., Nguyen, M. D., Corr, M., Tuck, S., and Raz, E. (2000) Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism. Nat Biotechnol 18, 509–514.PubMedCrossRefGoogle Scholar
  12. 12.
    Stevenson, F. K., Ottensmeier, C. H., Johnson, P., Zhu, D., Buchan, S. L., McCann, K. J., Roddick, J. S., King, A. T., McNicholl, F., Savelyeva, N., and Rice, J. (2004) DNA vaccines to attack cancer, Proc Natl Acad Sci U S A 101(2), 14646–14652.PubMedCrossRefGoogle Scholar
  13. 13.
    Stevenson, F. K., Rice, J., Ottensmeier, C. H., Thirdborough, S. M., and Zhu, D. (2004) DNA fusion gene vaccines against cancer: from the laboratory to the clinic. Immunol Rev 199, 156–180.PubMedCrossRefGoogle Scholar
  14. 14.
    McConkey, S. J., Reece, W. H., Moorthy, V. S., Webster, D., Dunachie, S., Butcher, G., Vuola, J. M., Blanchard, T. J., Gothard, P., Watkins, K., Hannan, C. M., Everaere, S., Brown, K., Kester, K. E., Cummings, J., Williams, J., Heppner, D. G., Pathan, A., Flanagan, K., Arulanantham, N., Roberts, M. T., Roy, M., Smith, G. L., Schneider, J., Peto, T., Sinden, R. E., Gilbert, S. C., and Hill, A. V. (2003) Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans. Nat Med 9, 729–735.PubMedCrossRefGoogle Scholar
  15. 15.
    Woodland, D. L. (2004) Jump-starting the immune system: prime-boosting comes of age. Trends Immunol 25, 98–104.PubMedCrossRefGoogle Scholar
  16. 16.
    Boczkowski, D., Nair, S. K., Snyder, D., and Gilboa, E. (1996) Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med 184, 465–472.PubMedCrossRefGoogle Scholar
  17. 17.
    Gottschalk, S., Edwards, O. L., Sili, U., Huls, M. H., Goltsova, T., Davis, A. R., Heslop, H. E., and Rooney, C. M. (2003) Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive immunotherapy of EBV-associated malignancies. Blood 101, 1905–1912.PubMedCrossRefGoogle Scholar
  18. 18.
    Holmes, L. M., Li, J., Sticca, R. P., Wagner, T. E., and Wei, Y. (2001) A Rapid, Novel Strategy to Induce Tumor Cell-Specific Cytotoxic T Lymphocyte Responses Using Instant Dendritomas. J Immunother (1991) 24, 122–129.CrossRefGoogle Scholar
  19. 19.
    Mackensen, A., Herbst, B., Chen, J. L., Kohler, G., Noppen, C., Herr, W., Spagnoli, G. C., Cerundolo, V., and Lindemann, A. (2000) Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34(+)() hematopoietic progenitor cells. Int J Cancer 86, 385–392.PubMedCrossRefGoogle Scholar
  20. 20.
    Radford, K. J., Jackson, A. M., Wang, J. H., Vassaux, G., and Lemoine, N. R. (2003) Recombinant E. coli efficiently delivers antigen and maturation signals to human dendritic cells: presentation of MART1 to CD8+ T cells. Int J Cancer 105, 811–819.PubMedCrossRefGoogle Scholar
  21. 21.
    Kikuchi, T., Akasaki, Y., Irie, M., Homma, S., Abe, T., and Ohno, T. (2001) Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells. Cancer Immunol Immunother 50, 337–344.PubMedCrossRefGoogle Scholar
  22. 22.
    Lin, A. M., Hershberg, R. M., and Small, E. J. (2006) Immunotherapy for prostate cancer using prostatic acid phosphatase loaded antigen presenting cells. Urol Oncol 24, 434–441.PubMedCrossRefGoogle Scholar
  23. 23.
    Small, E. J., Schellhammer, P. F., Higano, C. S., Redfern, C. H., Nemunaitis, J. J., Valone, F. H., Verjee, S. S., Jones, L. A., and Hershberg, R. M. (2006) Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24, 3089–3094.PubMedCrossRefGoogle Scholar
  24. 24.
    Moretta, L., Ferlazzo, G., Bottino, C., Vitale, M., Pende, D., Mingari, M. C., and Moretta, A. (2006) Effector and regulatory events during natural killer-dendritic cell interactions. Immunol Rev 214, 219–228.PubMedCrossRefGoogle Scholar
  25. 25.
    Degli-Esposti, M. A., and Smyth, M. J. (2005) Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat Rev Immunol 5, 112–124.PubMedCrossRefGoogle Scholar
  26. 26.
    Raulet, D. H. (2004) Interplay of natural killer cells and their receptors with the adaptive immune response. Nat Immunol 5, 996–1002.PubMedCrossRefGoogle Scholar
  27. 27.
    Becknell, B., and Caligiuri, M. A. (2005) Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv Immunol 86, 209–239.PubMedCrossRefGoogle Scholar
  28. 28.
    Rosenberg, S. A., Lotze, M. T., Muul, L. M., Leitman, S., Chang, A. E., Ettinghausen, S. E., Matory, Y. L., Skibber, J. M., Shiloni, E., Vetto, J. T., and et al. (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313, 1485–1492.PubMedCrossRefGoogle Scholar
  29. 29.
    Atkins, M. B., Lotze, M. T., Dutcher, J. P., Fisher, R. I., Weiss, G., Margolin, K., Abrams, J., Sznol, M., Parkinson, D., Hawkins, M., Paradise, C., Kunkel, L., and Rosenberg, S. A. (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17, 2105–2116.PubMedGoogle Scholar
  30. 30.
    Ruggeri, L., Capanni, M., Urbani, E., Perruccio, K., Shlomchik, W. D., Tosti, A., Posati, S., Rogaia, D., Frassoni, F., Aversa, F., Martelli, M. F., and Velardi, A. (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100.PubMedCrossRefGoogle Scholar
  31. 31.
    Bishop, M. R., Fowler, D. H., Marchigiani, D., Castro, K., Kasten-Sportes, C., Steinberg, S. M., Gea-Banacloche, J. C., Dean, R., Chow, C. K., Carter, C., Read, E. J., Leitman, S., and Gress, R. (2004) Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer. J Clin Oncol 22, 3886–3892.PubMedCrossRefGoogle Scholar
  32. 32.
    Horowitz, M. M., Gale, R. P., Sondel, P. M., Goldman, J. M., Kersey, J., Kolb, H. J., Rimm, A. A., Ringden, O., Rozman, C., Speck, B., and et al. (1990) Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75, 555–562.PubMedGoogle Scholar
  33. 33.
    Kolb, H. J., Mittermuller, J., Clemm, C., Holler, E., Ledderose, G., Brehm, G., Heim, M., and Wilmanns, W. (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76, 2462–2465.PubMedGoogle Scholar
  34. 34.
    Gilleece, M. H., and Dazzi, F. (2003) Donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukaemia. Leuk Lymphoma 44, 23–28.PubMedCrossRefGoogle Scholar
  35. 35.
    Kolb, H. J., Schattenberg, A., Goldman, J. M., Hertenstein, B., Jacobsen, N., Arcese, W., Ljungman, P., Ferrant, A., Verdonck, L., Niederwieser, D., van Rhee, F., Mittermueller, J., de Witte, T., Holler, E., and Ansari, H. (1995) Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86, 2041–2050.PubMedGoogle Scholar
  36. 36.
    Mackinnon, S., Papadopoulos, E. B., Carabasi, M. H., Reich, L., Collins, N. H., Boulad, F., Castro-Malaspina, H., Childs, B. H., Gillio, A. P., Kernan, N. A., and et al. (1995) Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood 86, 1261–1268.PubMedGoogle Scholar
  37. 37.
    Amrolia, P. J., Muccioli-Casadei, G., Yvon, E., Huls, H., Sili, U., Wieder, E. D., Bollard, C., Michalek, J., Ghetie, V., Heslop, H. E., Molldrem, J. J., Rooney, C. M., Schlinder, J., Vitetta, E., and Brenner, M. K. (2003) Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. Blood 102, 2292–2299.PubMedCrossRefGoogle Scholar
  38. 38.
    Solomon, S. R., Mielke, S., Savani, B. N., Montero, A., Wisch, L., Childs, R., Hensel, N., Schindler, J., Ghetie, V., Leitman, S. F., Mai, T., Carter, C. S., Kurlander, R., Read, E. J., Vitetta, E. S., and Barrett, A. J. (2005) Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation. Blood 106, 1123–1129.PubMedCrossRefGoogle Scholar
  39. 39.
    Bonini, C., Ferrari, G., Verzeletti, S., Servida, P., Zappone, E., Ruggieri, L., Ponzoni, M., Rossini, S., Mavilio, F., Traversari, C., and Bordignon, C. (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276, 1719–1724.PubMedCrossRefGoogle Scholar
  40. 40.
    Shariat, S. F., Desai, S., Song, W., Khan, T., Zhao, J., Nguyen, C., Foster, B. A., Greenberg, N., Spencer, D. M., and Slawin, K. M. (2001) Adenovirus-mediated transfer of inducible caspases: a novel “death switch” gene therapeutic approach to prostate cancer. Cancer Res 61, 2562–2571.PubMedGoogle Scholar
  41. 41.
    Straathof, K. C., Spencer, D. M., Sutton, R. E., and Rooney, C. M. (2003) Suicide genes as safety switches in T lymphocytes. Cytotherapy 5, 227–230.PubMedCrossRefGoogle Scholar
  42. 42.
    Thomis, D. C., Marktel, S., Bonini, C., Traversari, C., Gilman, M., Bordignon, C., and Clackson, T. (2001) A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood 97, 1249–1257.PubMedCrossRefGoogle Scholar
  43. 43.
    Tiberghien, P., Ferrand, C., Lioure, B., Milpied, N., Angonin, R., Deconinck, E., Certoux, J. M., Robinet, E., Saas, P., Petracca, B., Juttner, C., Reynolds, C. W., Longo, D. L., Herve, P., and Cahn, J. Y. (2001) Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood 97, 63–72.PubMedCrossRefGoogle Scholar
  44. 44.
    Ljunggren, H. G., and Karre, K. (1990) In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today 11, 237–244.PubMedCrossRefGoogle Scholar
  45. 45.
    Lanier, L. L. (1998) NK cell receptors. Annu Rev Immunol 16, 359–393.PubMedCrossRefGoogle Scholar
  46. 46.
    Parham, P. (2005) MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 5, 201–214.PubMedCrossRefGoogle Scholar
  47. 47.
    Farag, S. S., Bacigalupo, A., Eapen, M., Hurley, C., Dupont, B., Caligiuri, M. A., Boudreau, C., Nelson, G., Oudshoorn, M., van Rood, J., Velardi, A., Maiers, M., Setterholm, M., Confer, D., Posch, P. E., Anasetti, C., Kamani, N., Miller, J. S., Weisdorf, D., and Davies, S. M. (2006) The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biol Blood Marrow Transplant 12, 876–884.PubMedCrossRefGoogle Scholar
  48. 48.
    Passweg, J. R., Koehl, U., Uharek, L., Meyer-Monard, S., and Tichelli, A. (2006) Natural-killer-cell-based treatment in haematopoietic stem-cell transplantation. Best Pract Res Clin Haematol 19, 811–824.PubMedCrossRefGoogle Scholar
  49. 49.
    Ruggeri, L., Mancusi, A., Capanni, M., Urbani, E., Carotti, A., Aloisi, T., Stern, M., Pende, D., Perruccio, K., Burchielli, E., Topini, F., Bianchi, E., Aversa, F., Martelli, M. F., and Velardi, A. (2007) Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood 110, 433–440.PubMedCrossRefGoogle Scholar
  50. 50.
    Ljunggren, H. G., and Malmberg, K. J. (2007) Prospects for the use of NK cells in immunotherapy of human cancer. Nat Rev Immunol 7, 329–339.PubMedCrossRefGoogle Scholar
  51. 51.
    Riddell, S. R., Watanabe, K. S., Goodrich, J. M., Li, C. R., Agha, M. E., and Greenberg, P. D. (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257, 238–241.PubMedCrossRefGoogle Scholar
  52. 52.
    Einsele, H., Rauser, G., Grigoleit, U., Hebart, H., Sinzger, C., Riegler, S., and Jahn, G. (2002) Induction of CMV-specific T-cell lines using Ag-presenting cells pulsed with CMV protein or peptide. Cytotherapy 4, 49–54.PubMedCrossRefGoogle Scholar
  53. 53.
    Einsele, H., Roosnek, E., Rufer, N., Sinzger, C., Riegler, S., Loffler, J., Grigoleit, U., Moris, A., Rammensee, H. G., Kanz, L., Kleihauer, A., Frank, F., Jahn, G., and Hebart, H. (2002) Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood 99, 3916–3922.PubMedCrossRefGoogle Scholar
  54. 54.
    Walter, E. A., Greenberg, P. D., Gilbert, M. J., Finch, R. J., Watanabe, K. S., Thomas, E. D., and Riddell, S. R. (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333, 1038–1044.PubMedCrossRefGoogle Scholar
  55. 55.
    Heslop, H. E., Ng, C. Y., Li, C., Smith, C. A., Loftin, S. K., Krance, R. A., Brenner, M. K., and Rooney, C. M. (1996) Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med 2, 551–555.PubMedCrossRefGoogle Scholar
  56. 56.
    Leen, A. M., and Heslop, H. E. (2008) Cytotoxic T lymphocytes as immune-therapy in haematological practice. Br J Haematol 143, 169–179.PubMedCrossRefGoogle Scholar
  57. 57.
    Rooney, C. M., Smith, C. A., Ng, C. Y., Loftin, S., Li, C., Krance, R. A., Brenner, M. K., and Heslop, H. E. (1995) Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 345, 9–13.PubMedCrossRefGoogle Scholar
  58. 58.
    Gottschalk, S., Ng, C. Y., Perez, M., Smith, C. A., Sample, C., Brenner, M. K., Heslop, H. E., and Rooney, C. M. (2001) An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs. Blood 97, 835–843.PubMedCrossRefGoogle Scholar
  59. 59.
    Comoli, P., Basso, S., Zecca, M., Pagliara, D., Baldanti, F., Bernardo, M. E., Barberi, W., Moretta, A., Labirio, M., Paulli, M., Furione, M., Maccario, R., and Locatelli, F. (2007) Preemptive therapy of EBV-related lymphoproliferative disease after pediatric haploidentical stem cell transplantation. Am J Transplant 7, 1648–1655.PubMedCrossRefGoogle Scholar
  60. 60.
    Gustafsson, A., Levitsky, V., Zou, J. Z., Frisan, T., Dalianis, T., Ljungman, P., Ringden, O., Winiarski, J., Ernberg, I., and Masucci, M. G. (2000) Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood 95, 807–814.PubMedGoogle Scholar
  61. 61.
    Imashuku, S., Goto, T., Matsumura, T., Naya, M., Yamori, M., Hojo, M., Hibi, S., and Todo, S. (1997) Unsuccessful CTL transfusion in a case of post-BMT Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD). Bone Marrow Transplant 20, 337–340.PubMedCrossRefGoogle Scholar
  62. 62.
    O’Reilly, R. J., Doubrovina, E., Trivedi, D., Hasan, A., Kollen, W., and Koehne, G. (2007) Adoptive transfer of antigen-specific T-cells of donor type for immunotherapy of viral infections following allogeneic hemato-poietic cell transplants. Immunol Res 38, 237–250.PubMedCrossRefGoogle Scholar
  63. 63.
    Haque, T., Wilkie, G. M., Taylor, C., Amlot, P. L., Murad, P., Iley, A., Dombagoda, D., Britton, K. M., Swerdlow, A. J., and Crawford, D. H. (2002) Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet 360, 436–442.PubMedCrossRefGoogle Scholar
  64. 64.
    Haque, T., Wilkie, G. M., Jones, M. M., Higgins, C. D., Urquhart, G., Wingate, P., Burns, D., McAulay, K., Turner, M., Bellamy, C., Amlot, P. L., Kelly, D., MacGilchrist, A., Gandhi, M. K., Swerdlow, A. J., and Crawford, D. H. (2007) Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood 110, 1123–1131.PubMedCrossRefGoogle Scholar
  65. 65.
    Bollard, C. M., Gottschalk, S., Leen, A. M., Weiss, H., Straathof, K. C., Carrum, G., Khalil, M., Wu, M. F., Huls, M. H., Chang, C. C., Gresik, M. V., Gee, A. P., Brenner, M. K., Rooney, C. M., and Heslop, H. E. (2007) Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. Blood 110, 2838–2845.PubMedCrossRefGoogle Scholar
  66. 66.
    Niedobitek, G. (2000) Epstein-Barr virus infection in the pathogenesis of nasopharyngeal carcinoma. Mol Pathol 53, 248–254.PubMedCrossRefGoogle Scholar
  67. 67.
    Chua, D., Huang, J., Zheng, B., Lau, S. Y., Luk, W., Kwong, D. L., Sham, J. S., Moss, D., Yuen, K. Y., Im, S. W., and Ng, M. H. (2001) Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T cells for nasopharyngeal carcinoma. Int J Cancer 94, 73–80.PubMedCrossRefGoogle Scholar
  68. 68.
    Straathof, K. C., Bollard, C. M., Popat, U., Huls, M. H., Lopez, T., Morriss, M. C., Gresik, M. V., Gee, A. P., Russell, H. V., Brenner, M. K., Rooney, C. M., and Heslop, H. E. (2005) Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes. Blood 105, 1898–1904.PubMedCrossRefGoogle Scholar
  69. 69.
    Louis, C. U., Straathof, K., Bollard, C. M., Gerken, C., Huls, M. H., Gresik, M. V., Wu, M. F., Weiss, H. L., Gee, A. P., Brenner, M. K., Rooney, C. M., Heslop, H. E., and Gottschalk, S. (2009) Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients. Blood 113, 2442–2450.PubMedCrossRefGoogle Scholar
  70. 70.
    Stevenson, F. K., Rice, J., and Zhu, D. (2004) Tumor vaccines. Adv Immunol 82, 49–103.PubMedCrossRefGoogle Scholar
  71. 71.
    Yee, C., Thompson, J. A., Byrd, D., Riddell, S. R., Roche, P., Celis, E., and Greenberg, P. D. (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci U S A 99, 16168–16173.PubMedCrossRefGoogle Scholar
  72. 72.
    Ochsenbein, A. F., Klenerman, P., Karrer, U., Ludewig, B., Pericin, M., Hengartner, H., and Zinkernagel, R. M. (1999) Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci U S A 96, 2233–2238.PubMedCrossRefGoogle Scholar
  73. 73.
    Teague, R. M., Sather, B. D., Sacks, J. A., Huang, M. Z., Dossett, M. L., Morimoto, J., Tan, X., Sutton, S. E., Cooke, M. P., Ohlen, C., and Greenberg, P. D. (2006) Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med 12, 335–341.PubMedCrossRefGoogle Scholar
  74. 74.
    Dembic, Z., Haas, W., Weiss, S., McCubrey, J., Kiefer, H., von Boehmer, H., and Steinmetz, M. (1986) Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320, 232–238.PubMedCrossRefGoogle Scholar
  75. 75.
    Kessels, H. W., Wolkers, M. C., van den Boom, M. D., van der Valk, M. A., and Schumacher, T. N. (2001) Immunotherapy through TCR gene transfer. Nat Immunol 2, 957–961.PubMedCrossRefGoogle Scholar
  76. 76.
    Xue, S. A., Gao, L., Hart, D., Gillmore, R., Qasim, W., Thrasher, A., Apperley, J., Engels, B., Uckert, W., Morris, E., and Stauss, H. (2005) Elimination of human leukemia cells in NOD/SCID mice by WT1-TCR gene-transduced human T cells. Blood 106, 3062–3067.PubMedCrossRefGoogle Scholar
  77. 77.
    Morgan, R. A., Dudley, M. E., Wunderlich, J. R., Hughes, M. S., Yang, J. C., Sherry, R. M., Royal, R. E., Topalian, S. L., Kammula, U. S., Restifo, N. P., Zheng, Z., Nahvi, A., de Vries, C. R., Rogers-Freezer, L. J., Mavroukakis, S. A., and Rosenberg, S. A. (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129.PubMedCrossRefGoogle Scholar
  78. 78.
    Heemskerk, M. H., Hoogeboom, M., de Paus, R. A., Kester, M. G., van der Hoorn, M. A., Goulmy, E., Willemze, R., and Falkenburg, J. H. (2003) Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region. Blood 102, 3530–3540.PubMedCrossRefGoogle Scholar
  79. 79.
    Mutis, T., Blokland, E., Kester, M., Schrama, E., and Goulmy, E. (2002) Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules: a potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation. Blood 100, 547–552.PubMedCrossRefGoogle Scholar
  80. 80.
    Stanislawski, T., Voss, R. H., Lotz, C., Sadovnikova, E., Willemsen, R. A., Kuball, J., Ruppert, T., Bolhuis, R. L., Melief, C. J., Huber, C., Stauss, H. J., and Theobald, M. (2001) Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol 2, 962–970.PubMedCrossRefGoogle Scholar
  81. 81.
    Gross, G., Waks, T., and Eshhar, Z. (1989) Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A 86, 10024–10028.PubMedCrossRefGoogle Scholar
  82. 82.
    Kershaw, M. H., Darcy, P. K., Trapani, J. A., and Smyth, M. J. (1996) The use of chimeric human Fc(epsilon) receptor I to redirect cytotoxic T lymphocytes to tumors. J Leukoc Biol 60, 721–728.PubMedGoogle Scholar
  83. 83.
    Kershaw, M. H., Westwood, J. A., Parker, L. L., Wang, G., Eshhar, Z., Mavroukakis, S. A., White, D. E., Wunderlich, J. R., Canevari, S., Rogers-Freezer, L., Chen, C. C., Yang, J. C., Rosenberg, S. A., and Hwu, P. (2006) A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12, 6106–6115.PubMedCrossRefGoogle Scholar
  84. 84.
    Lamers, C. H., Sleijfer, S., Vulto, A. G., Kruit, W. H., Kliffen, M., Debets, R., Gratama, J. W., Stoter, G., and Oosterwijk, E. (2006) Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 24, e20–22.PubMedCrossRefGoogle Scholar
  85. 85.
    Till, B. G., Jensen, M. C., Wang, J., Chen, E. Y., Wood, B. L., Greisman, H. A., Qian, X., James, S. E., Raubitschek, A., Forman, S. J., Gopal, A. K., Pagel, J. M., Lindgren, C. G., Greenberg, P. D., Riddell, S. R., and Press, O. W. (2008) Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112, 2261–2271.PubMedCrossRefGoogle Scholar
  86. 86.
    Finney, H. M., Akbar, A. N., and Lawson, A. D. (2004) Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol 172, 104–113.PubMedGoogle Scholar
  87. 87.
    Maher, J., Brentjens, R. J., Gunset, G., Riviere, I., and Sadelain, M. (2002) Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol 20, 70–75.PubMedCrossRefGoogle Scholar
  88. 88.
    Pule, M. A., Savoldo, B., Myers, G. D., Rossig, C., Russell, H. V., Dotti, G., Huls, M. H., Liu, E., Gee, A. P., Mei, Z., Yvon, E., Weiss, H. L., Liu, H., Rooney, C. M., Heslop, H. E., and Brenner, M. K. (2008) Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14, 1264–1270.PubMedCrossRefGoogle Scholar
  89. 89.
    Siegel, P. M., and Massague, J. (2003) Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3, 807–821.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhang, Q., Yang, X., Pins, M., Javonovic, B., Kuzel, T., Kim, S. J., Parijs, L. V., Greenberg, N. M., Liu, V., Guo, Y., and Lee, C. (2005) Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. Cancer Res 65, 1761–1769.PubMedCrossRefGoogle Scholar
  91. 91.
    Bollard, C. M., Rossig, C., Calonge, M. J., Huls, M. H., Wagner, H. J., Massague, J., Brenner, M. K., Heslop, H. E., and Rooney, C. M. (2002) Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity. Blood 99, 3179–3187.PubMedCrossRefGoogle Scholar
  92. 92.
    Hsu, C., Hughes, M. S., Zheng, Z., Bray, R. B., Rosenberg, S. A., and Morgan, R. A. (2005) Primary human T lymphocytes engineered with a codon-optimized IL-15 gene resist cytokine withdrawal-induced apoptosis and persist long-term in the absence of exogenous cytokine. J Immunol 175, 7226–7234.PubMedGoogle Scholar
  93. 93.
    Heemskerk, B., Liu, K., Dudley, M. E., Johnson, L. A., Kaiser, A., Downey, S., Zheng, Z., Shelton, T. E., Matsuda, K., Robbins, P. F., Morgan, R. A., and Rosenberg, S. A. (2008) Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum Gene Ther 19, 496–510.PubMedCrossRefGoogle Scholar
  94. 94.
    Vera, J. F., Hoyos, V., Savoldo, B., Quintarelli, C., Giordano Attianese, G. M., Leen, A. M., Liu, H., Foster, A. E., Heslop, H. E., Rooney, C. M., Brenner, M. K., and Dotti, G. (2009) Genetic Manipulation of Tumor-specific Cytotoxic T Lymphocytes to Restore Responsiveness to IL-7. Mol Ther.Google Scholar
  95. 95.
    Gattinoni, L., Powell, D. J., Jr., Rosenberg, S. A., and Restifo, N. P. (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6, 383–393.PubMedCrossRefGoogle Scholar
  96. 96.
    Wagner, H. J., Bollard, C. M., Vigouroux, S., Huls, M. H., Anderson, R., Prentice, H. G., Brenner, M. K., Heslop, H. E., and Rooney, C. M. (2004) A strategy for treatment of Epstein-Barr virus-positive Hodgkin’s disease by targeting interleukin 12 to the tumor environment using tumor antigen-specific T cells. Cancer Gene Ther 11, 81–91.PubMedCrossRefGoogle Scholar
  97. 97.
    Cuenca, A., Cheng, F., Wang, H., Brayer, J., Horna, P., Gu, L., Bien, H., Borrello, I. M., Levitsky, H. I., and Sotomayor, E. M. (2003) Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens. Cancer Res 63, 9007–9015.PubMedGoogle Scholar
  98. 98.
    Staveley-O’Carroll, K., Sotomayor, E., Montgomery, J., Borrello, I., Hwang, L., Fein, S., Pardoll, D., and Levitsky, H. (1998) Induction of antigen-specific T cell anergy: An early event in the course of tumor progression. Proc Natl Acad Sci USA 95, 1178–1183.PubMedCrossRefGoogle Scholar
  99. 99.
    Horna, P., Cuenca, A., Cheng, F., Brayer, J., Wang, H. W., Borrello, I., Levitsky, H., and Sotomayor, E. M. (2006) In vivo disruption of tolerogenic cross-presentation mechanisms uncovers an effective T-cell activation by B-cell lymphomas leading to antitumor immunity. Blood 107, 2871–2878.PubMedCrossRefGoogle Scholar
  100. 100.
    Sotomayor, E. M., Borrello, I., Rattis, F. M., Cuenca, A. G., Abrams, J., Staveley-O’Carroll, K., and Levitsky, H. I. (2001) Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood 98, 1070–1077.PubMedCrossRefGoogle Scholar
  101. 101.
    Koneru, M., Schaer, D., Monu, N., Ayala, A., and Frey, A. B. (2005) Defective proximal TCR signaling inhibits CD8+ tumor-infiltrating lymphocyte lytic function. J Immunol 174, 1830–1840.PubMedGoogle Scholar
  102. 102.
    Mizoguchi, H., O’Shea, J. J., Longo, D. L., Loeffler, C. M., McVicar, D. W., and Ochoa, A. C. (1992) Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258, 1795–1798.PubMedCrossRefGoogle Scholar
  103. 103.
    Whiteside, T. L. (2006) Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Semin Cancer Biol 16, 3–15.PubMedCrossRefGoogle Scholar
  104. 104.
    Marincola, F. M., Jaffee, E. M., Hicklin, D. J., and Ferrone, S. (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74, 181–273.PubMedCrossRefGoogle Scholar
  105. 105.
    Rivoltini, L., Carrabba, M., Huber, V., Castelli, C., Novellino, L., Dalerba, P., Mortarini, R., Arancia, G., Anichini, A., Fais, S., and Parmiani, G. (2002) Immunity to cancer: attack and escape in T lymphocyte-tumor cell interaction. Immunol Rev 188, 97–113.PubMedCrossRefGoogle Scholar
  106. 106.
    Blank, C., Gajewski, T. F., and Mackensen, A. (2005) Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother 54, 307–314.PubMedCrossRefGoogle Scholar
  107. 107.
    Kryczek, I., Zou, L., Rodriguez, P., Zhu, G., Wei, S., Mottram, P., Brumlik, M., Cheng, P., Curiel, T., Myers, L., Lackner, A., Alvarez, X., Ochoa, A., Chen, L., and Zou, W. (2006) B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 203, 871–881.PubMedCrossRefGoogle Scholar
  108. 108.
    Leach, D. R., Krummel, M. F., and Allison, J. P. (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736.PubMedCrossRefGoogle Scholar
  109. 109.
    Watanabe, N., Gavrieli, M., Sedy, J. R., Yang, J., Fallarino, F., Loftin, S. K., Hurchla, M. A., Zimmerman, N., Sim, J., Zang, X., Murphy, T. L., Russell, J. H., Allison, J. P., and Murphy, K. M. (2003) BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 4, 670–679.PubMedCrossRefGoogle Scholar
  110. 110.
    Akasaki, Y., Liu, G., Chung, N. H., Ehtesham, M., Black, K. L., and Yu, J. S. (2004) Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. J Immunol 173, 4352–4359.PubMedGoogle Scholar
  111. 111.
    Gabrilovich, D. I., Chen, H. L., Girgis, K. R., Cunningham, H. T., Meny, G. M., Nadaf, S., Kavanaugh, D., and Carbone, D. P. (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2, 1096–1103.PubMedCrossRefGoogle Scholar
  112. 112.
    Gerlini, G., Tun-Kyi, A., Dudli, C., Burg, G., Pimpinelli, N., and Nestle, F. O. (2004) Metastatic melanoma secreted IL-10 down-regulates CD1 molecules on dendritic cells in metastatic tumor lesions. Am J Pathol 165, 1853–1863.PubMedCrossRefGoogle Scholar
  113. 113.
    Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K., and Flavell, R. A. (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24, 99–146.PubMedCrossRefGoogle Scholar
  114. 114.
    Waldmann, T. A. (2006) Effective cancer therapy through immunomodulation. Annu Rev Med 57, 65–81.PubMedCrossRefGoogle Scholar
  115. 115.
    Andreola, G., Rivoltini, L., Castelli, C., Huber, V., Perego, P., Deho, P., Squarcina, P., Accornero, P., Lozupone, F., Lugini, L., Stringaro, A., Molinari, A., Arancia, G., Gentile, M., Parmiani, G., and Fais, S. (2002) Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 195, 1303–1316.PubMedCrossRefGoogle Scholar
  116. 116.
    Giovarelli, M., Musiani, P., Garotta, G., Ebner, R., Di Carlo, E., Kim, Y., Cappello, P., Rigamonti, L., Bernabei, P., Novelli, F., Modesti, A., Coletti, A., Ferrie, A. K., Lollini, P. L., Ruben, S., Salcedo, T., and Forni, G. (1999) A “stealth effect”: adenocarcinoma cells engineered to express TRAIL elude tumor-specific and allogeneic T cell reactions. J Immunol 163, 4886–4893.PubMedGoogle Scholar
  117. 117.
    Hahne, M., Rimoldi, D., Schroter, M., Romero, P., Schreier, M., French, L. E., Schneider, P., Bornand, T., Fontana, A., Lienard, D., Cerottini, J., and Tschopp, J. (1996) Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274, 1363–1366.PubMedCrossRefGoogle Scholar
  118. 118.
    O’Connell, J., Houston, A., Bennett, M. W., O’Sullivan, G. C., and Shanahan, F. (2001) Immune privilege or inflammation? Insights into the Fas ligand enigma. Nat Med 7, 271–274.PubMedCrossRefGoogle Scholar
  119. 119.
    Perillo, N. L., Pace, K. E., Seilhamer, J. J., and Baum, L. G. (1995) Apoptosis of T cells mediated by galectin-1. Nature 378, 736–739.PubMedCrossRefGoogle Scholar
  120. 120.
    Uyttenhove, C., Pilotte, L., Theate, I., Stroobant, V., Colau, D., Parmentier, N., Boon, T., and Van den Eynde, B. J. (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9, 1269–1274.PubMedCrossRefGoogle Scholar
  121. 121.
    Almand, B., Resser, J. R., Lindman, B., Nadaf, S., Clark, J. I., Kwon, E. D., Carbone, D. P., and Gabrilovich, D. I. (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6, 1755–1766.PubMedGoogle Scholar
  122. 122.
    Colonna, M., Trinchieri, G., and Liu, Y. J. (2004) Plasmacytoid dendritic cells in immunity. Nat Immunol 5, 1219–1226.PubMedCrossRefGoogle Scholar
  123. 123.
    Gabrilovich, D. I., Velders, M. P., Sotomayor, E. M., and Kast, W. M. (2001) Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 166, 5398–5406.PubMedGoogle Scholar
  124. 124.
    Kusmartsev, S., Nagaraj, S., and Gabrilovich, D. I. (2005) Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol 175, 4583–4592.PubMedGoogle Scholar
  125. 125.
    Li, Q., Pan, P. Y., Gu, P., Xu, D., and Chen, S. H. (2004) Role of immature myeloid Gr-1+ cells in the development of antitumor immunity. Cancer Res 64, 1130–1139.PubMedCrossRefGoogle Scholar
  126. 126.
    Munn, D. H., Sharma, M. D., Hou, D., Baban, B., Lee, J. R., Antonia, S. J., Messina, J. L., Chandler, P., Koni, P. A., and Mellor, A. L. (2004) Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 114, 280–290.PubMedGoogle Scholar
  127. 127.
    Munn, D. H., Sharma, M. D., Lee, J. R., Jhaver, K. G., Johnson, T. S., Keskin, D. B., Marshall, B., Chandler, P., Antonia, S. J., Burgess, R., Slingluff, C. L., Jr., and Mellor, A. L. (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297, 1867–1870.PubMedCrossRefGoogle Scholar
  128. 128.
    Pinzon-Charry, A., Ho, C. S., Laherty, R., Maxwell, T., Walker, D., Gardiner, R. A., O’Connor, L., Pyke, C., Schmidt, C., Furnival, C., and Lopez, J. A. (2005) A population of HLA-DR+ immature cells accumulates in the blood dendritic cell compartment of patients with different types of cancer. Neoplasia 7, 1112–1122.PubMedCrossRefGoogle Scholar
  129. 129.
    Pinzon-Charry, A., Maxwell, T., Prato, S., Furnival, C., Schmidt, C., and Lopez, J. A. (2005) HLA-DR+ immature cells exhibit reduced antigen-presenting cell function but respond to CD40 stimulation. Neoplasia 7, 1123–1132.PubMedCrossRefGoogle Scholar
  130. 130.
    Sakaguchi, S. (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22, 531–562.PubMedCrossRefGoogle Scholar
  131. 131.
    Zou, W. (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5, 263–274.PubMedCrossRefGoogle Scholar
  132. 132.
    Angulo, I., de las Heras, F. G., Garcia-Bustos, J. F., Gargallo, D., Munoz-Fernandez, M. A., and Fresno, M. (2000) Nitric oxide-producing CD11b(+)Ly-6G(Gr-1)(+)CD31(ER-MP12)(+) cells in the spleen of cyclophosphamide-treated mice: implications for T-cell responses in immunosuppressed mice. Blood 95, 212–220.PubMedGoogle Scholar
  133. 133.
    Mackall, C. L., Fleisher, T. A., Brown, M. R., Magrath, I. T., Shad, A. T., Horowitz, M. E., Wexler, L. H., Adde, M. A., McClure, L. L., and Gress, R. E. (1994) Lymphocyte depletion during treatment with intensive chemotherapy for cancer. Blood 84, 2221–2228.PubMedGoogle Scholar
  134. 134.
    Mohty, M., Gaugler, B., Faucher, C., Sainty, D., Lafage-Pochitaloff, M., Vey, N., Bouabdallah, R., Arnoulet, C., Gastaut, J. A., Viret, F., Wolfers, J., Maraninchi, D., Blaise, D., and Olive, D. (2002) Recovery of lymphocyte and dendritic cell subsets following reduced intensity allogeneic bone marrow transplantation. Hematology 7, 157–164.PubMedCrossRefGoogle Scholar
  135. 135.
    Santosuosso, M., Divangahi, M., Zganiacz, A., and Xing, Z. (2002) Reduced tissue macrophage population in the lung by anticancer agent cyclophosphamide: restoration by local granulocyte macrophage-colony-stimulating factor gene transfer. Blood 99, 1246–1252.PubMedCrossRefGoogle Scholar
  136. 136.
    Hakim, F. T., Cepeda, R., Kaimei, S., Mackall, C. L., McAtee, N., Zujewski, J., Cowan, K., and Gress, R. E. (1997) Constraints on CD4 recovery postchemotherapy in adults: thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells. Blood 90, 3789–3798.PubMedGoogle Scholar
  137. 137.
    Mackall, C. L., Fleisher, T. A., Brown, M. R., Andrich, M. P., Chen, C. C., Feuerstein, I. M., Horowitz, M. E., Magrath, I. T., Shad, A. T., Steinberg, S. M., and et al. (1995) Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 332, 143–149.PubMedCrossRefGoogle Scholar
  138. 138.
    Mackall, C. L., Fleisher, T. A., Brown, M. R., Andrich, M. P., Chen, C. C., Feuerstein, I. M., Magrath, I. T., Wexler, L. H., Dimitrov, D. S., and Gress, R. E. (1997) Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy. Blood 89, 3700–3707.PubMedGoogle Scholar
  139. 139.
    Kirkwood, J. M., Ibrahim, J., Lawson, D. H., Atkins, M. B., Agarwala, S. S., Collins, K., Mascari, R., Morrissey, D. M., and Chapman, P. B. (2001) High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696. J Clin Oncol 19, 1430–1436.PubMedGoogle Scholar
  140. 140.
    Miles, D., and Papazisis, K. (2003) Rationale for the clinical development of STn-KLH (Theratope) and anti-MUC-1 vaccines in breast cancer. Clin Breast Cancer. Suppl 4, S134–138.Google Scholar
  141. 141.
    Ibrahim, N. (2004) Humoral immune responses to naturally occuring STn in metastatic breast cancer patients (MBC pts) treated with STn-KLH vaccine (abstract). Prom Am Soc Clin Oncol 23.Google Scholar
  142. 142.
    Mayordoma, J. (2004) Long term follow up of patients concomitantly treated with hormone therapy in prospective controlled randomized multicenter clinical study comparing STn-KLH avccine with KLH control in stage IV breast cancer following first line chemotherapy (abstract). Prom Am Soc Clin Oncol 23.Google Scholar
  143. 143.
    De Marco, F., Hallez, S., Brulet, J. M., Gesche, F., Marzano, P., Flamini, S., Marcante, M. L., and Venuti, A. (2003) DNA vaccines against HPV-16 E7-expressing tumour cells. Anticancer Res 23, 1449–1454.PubMedGoogle Scholar
  144. 144.
    Kim, D., Hoory, T., Wu, T. C., and Hung, C. F. (2007) Enhancing DNA vaccine potency by combining a strategy to prolong dendritic cell life and intracellular targeting strategies with a strategy to boost CD4+ T cell. Hum Gene Ther 18, 1129–1139.PubMedCrossRefGoogle Scholar
  145. 145.
    Yu, M., and Finn, O. J. (2006) DNA vaccines for cancer too. Cancer Immunol Immunother 55, 119–130.PubMedCrossRefGoogle Scholar
  146. 146.
    Baskar, S., Nabavi, N., Glimcher, L. H., and Ostrand-Rosenberg, S. (1993) Tumor cells expressing major histocompatibility complex class II and B7 activation molecules stimulate potent tumor-specific immunity. J Immunother Emphasis Tumor Immunol 14, 209–215.PubMedCrossRefGoogle Scholar
  147. 147.
    Berd, D., Maguire, H. C., Jr., McCue, P., and Mastrangelo, M. J. (1990) Treatment of metastatic melanoma with an autologous tumor-cell vaccine: clinical and immunologic results in 64 patients. J Clin Oncol 8, 1858–1867.PubMedGoogle Scholar
  148. 148.
    Dols, A., Smith, J. W., 2nd, Meijer, S. L., Fox, B. A., Hu, H. M., Walker, E., Rosenheim, S., Moudgil, T., Doran, T., Wood, W., Seligman, M., Alvord, W. G., Schoof, D., and Urba, W. J. (2003) Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: clinical and immunological results. Hum Gene Ther 14, 1117–1123.PubMedCrossRefGoogle Scholar
  149. 149.
    Michael, A., Ball, G., Quatan, N., Wushishi, F., Russell, N., Whelan, J., Chakraborty, P., Leader, D., Whelan, M., and Pandha, H. (2005) Delayed disease progression after allogeneic cell vaccination in hormone-resistant prostate cancer and correlation with immunologic variables. Clin Cancer Res 11, 4469–4478.PubMedCrossRefGoogle Scholar
  150. 150.
    Mitchell, M. S., Kan-Mitchell, J., Kempf, R. A., Harel, W., Shau, H. Y., and Lind, S. (1988) Active specific immunotherapy for melanoma: phase I trial of allogeneic lysates and a novel adjuvant. Cancer Res 48, 5883–5893.PubMedGoogle Scholar
  151. 151.
    Raez, L. E., Cassileth, P. A., Schlesselman, J. J., Sridhar, K., Padmanabhan, S., Fisher, E. Z., Baldie, P. A., and Podack, E. R. (2004) Allogeneic vaccination with a B7.1 HLA-A gene-modified adenocarcinoma cell line in patients with advanced non-small-cell lung cancer. J Clin Oncol 22, 2800–2807.PubMedCrossRefGoogle Scholar
  152. 152.
    Townsend, S. E., and Allison, J. P. (1993) Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells. Science 259, 368–370.PubMedCrossRefGoogle Scholar
  153. 153.
    Vermorken, J. B., Claessen, A. M., van Tinteren, H., Gall, H. E., Ezinga, R., Meijer, S., Scheper, R. J., Meijer, C. J., Bloemena, E., Ransom, J. H., Hanna, M. G., Jr., and Pinedo, H. M. (1999) Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet 353, 345–350.PubMedCrossRefGoogle Scholar
  154. 154.
    Boczkowski, D., Nair, S. K., Nam, J. H., Lyerly, H. K., and Gilboa, E. (2000) Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells. Cancer Res 60, 1028–1034.PubMedGoogle Scholar
  155. 155.
    Chen, Z., Moyana, T., Saxena, A., Warrington, R., Jia, Z., and Xiang, J. (2001) Efficient antitumor immunity derived from maturation of dendritic cells that had phagocytosed apoptotic/necrotic tumor cells. Int J Cancer 93, 539–548.PubMedCrossRefGoogle Scholar
  156. 156.
    Di Nicola, M., Carlo-Stella, C., Milanesi, M., Magni, M., Longoni, P., Mortarini, R., Anichini, A., Tomanin, R., Scarpa, M., and Gianni, A. M. (2000) Large-scale feasibility of gene transduction into human CD34+ cell-derived dendritic cells by adenoviral/polycation complex. Br J Haematol 111, 344–350.PubMedCrossRefGoogle Scholar
  157. 157.
    Galea-Lauri, J., Wells, J. W., Darling, D., Harrison, P., and Farzaneh, F. (2004) Strategies for antigen choice and priming of dendritic cells influence the polarization and efficacy of antitumor T-cell responses in dendritic cell-based cancer vaccination. Cancer Immunol Immunother 53, 963–977.PubMedCrossRefGoogle Scholar
  158. 158.
    Gong, J., Nikrui, N., Chen, D., Koido, S., Wu, Z., Tanaka, Y., Cannistra, S., Avigan, D., and Kufe, D. (2000) Fusions of human ovarian carcinoma cells with autologous or allogeneic dendritic cells induce antitumor immunity. J Immunol 165, 1705–1711.PubMedGoogle Scholar
  159. 159.
    He, Y., Zhang, J., Mi, Z., Robbins, P., and Falo, L. D., Jr. (2005) Immunization with lentiviral vector-transduced dendritic cells induces strong and long-lasting T cell responses and therapeutic immunity. J Immunol 174, 3808–3817.PubMedGoogle Scholar
  160. 160.
    Koido, S., Ohana, M., Liu, C., Nikrui, N., Durfee, J., Lerner, A., and Gong, J. (2004) Dendritic cells fused with human cancer cells: morphology, antigen expression, and T cell stimulation. Clin Immunol 113, 261–269.PubMedCrossRefGoogle Scholar
  161. 161.
    Li, Y., Bendandi, M., Deng, Y., Dunbar, C., Munshi, N., Jagannath, S., Kwak, L. W., and Lyerly, H. K. (2000) Tumor-specific recognition of human myeloma cells by idiotype-induced CD8(+) T cells. Blood 96, 2828–2833.PubMedGoogle Scholar
  162. 162.
    Muller, M. R., Grunebach, F., Nencioni, A., and Brossart, P. (2003) Transfection of dendritic cells with RNA induces CD4- and CD8-mediated T cell immunity against breast carcinomas and reveals the immunodominance of presented T cell epitopes. J Immunol 170, 5892–5896.PubMedGoogle Scholar
  163. 163.
    Strobel, I., Berchtold, S., Gotze, A., Schulze, U., Schuler, G., and Steinkasserer, A. (2000) Human dendritic cells transfected with either RNA or DNA encoding influenza matrix protein M1 differ in their ability to stimulate cytotoxic T lymphocytes. Gene Ther 7, 2028–2035.PubMedCrossRefGoogle Scholar
  164. 164.
    Timmerman, J. M., Czerwinski, D. K., Davis, T. A., Hsu, F. J., Benike, C., Hao, Z. M., Taidi, B., Rajapaksa, R., Caspar, C. B., Okada, C. Y., van Beckhoven, A., Liles, T. M., Engleman, E. G., and Levy, R. (2002) Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood 99, 1517–1526.PubMedCrossRefGoogle Scholar
  165. 165.
    Titzer, S., Christensen, O., Manzke, O., Tesch, H., Wolf, J., Emmerich, B., Carsten, C., Diehl, V., and Bohlen, H. (2000) Vaccination of multiple myeloma patients with idiotype-pulsed dendritic cells: immunological and clinical aspects. Br J Haematol 108, 805–816.PubMedCrossRefGoogle Scholar
  166. 166.
    Biagi, E., Rousseau, R., Yvon, E., Schwartz, M., Dotti, G., Foster, A., Havlik-Cooper, D., Grilley, B., Gee, A., Baker, K., Carrum, G., Rice, L., Andreeff, M., Popat, U., and Brenner, M. (2005) Responses to human CD40 ligand/human interleukin-2 autologous cell vaccine in patients with B-cell chronic lymphocytic leukemia. Clin Cancer Res 11, 6916–6923.PubMedCrossRefGoogle Scholar
  167. 167.
    Eguchi, J., Kuwashima, N., Hatano, M., Nishimura, F., Dusak, J. E., Storkus, W. J., and Okada, H. (2005) IL-4-transfected tumor cell vaccines activate tumor-infiltrating dendritic cells and promote type-1 immunity. J Immunol 174, 7194–7201.PubMedGoogle Scholar
  168. 168.
    Kusumoto, M., Umeda, S., Ikubo, A., Aoki, Y., Tawfik, O., Oben, R., Williamson, S., Jewell, W., and Suzuki, T. (2001) Phase 1 clinical trial of irradiated autologous melanoma cells adenovirally transduced with human GM-CSF gene. Cancer Immunol Immunother 50, 373–381.PubMedCrossRefGoogle Scholar
  169. 169.
    Pandha, H., Eaton, J., Greenhalgh, R., Soars, D., and Dalgleish, A. (2005) Immunotherapy of murine prostate cancer using whole tumor cells killed ex vivo by herpes simplex viral thymidine kinase/ganciclovir suicide gene therapy. Cancer Gene Ther 12, 572–578.PubMedCrossRefGoogle Scholar
  170. 170.
    Pericle, F., Giovarelli, M., Colombo, M. P., Ferrari, G., Musiani, P., Modesti, A., Cavallo, F., Di Pierro, F., Novelli, F., and Forni, G. (1994) An efficient Th2-type memory follows CD8+ lymphocyte-driven and eosinophil-mediated rejection of a spontaneous mouse mammary adenocarcinoma engineered to release IL-4. J Immunol 153, 5659–5673.PubMedGoogle Scholar
  171. 171.
    Rousseau, R. F., Biagi, E., Dutour, A., Yvon, E. S., Brown, M. P., Lin, T., Mei, Z., Grilley, B., Popek, E., Heslop, H. E., Gee, A. P., Krance, R. A., Popat, U., Carrum, G., Margolin, J. F., and Brenner, M. K. (2006) Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. Blood 107, 1332–1341.PubMedCrossRefGoogle Scholar
  172. 172.
    Schirrmacher, V. (2005) Clinical trials of antitumor vaccination with an autologous tumor cell vaccine modified by virus infection: improvement of patient survival based on improved antitumor immune memory. Cancer Immunol Immunother 54, 587–598.PubMedCrossRefGoogle Scholar
  173. 173.
    Brenner, M. K., Heslop, H., Krance, R., Horowitz, M., Strother, D., Nuchtern, J., Grilley, B., Martingano, E., and Cooper, K. (2000) Phase I study of chemokine and cytokine gene-modified autologous neuroblastoma cells for treatment of relapsed/refractory neuroblastoma using an adenoviral vector. Hum Gene Ther 11, 1477–1488.PubMedCrossRefGoogle Scholar
  174. 174.
    Dilloo, D., Bacon, K., Holden, W., Zhong, W., Burdach, S., Zlotnik, A., and Brenner, M. (1996) Combined chemokine and cytokine gene transfer enhances antitumor immunity. Nat Med 2, 1090–1095.PubMedCrossRefGoogle Scholar
  175. 175.
    Abdel-Wahab, Z., Dar, M., Osanto, S., Fong, T., Vervaert, C. E., Hester, D., Jolly, D., and Seigler, H. F. (1997) Eradication of melanoma pulmonary metastases by immunotherapy with tumor cells engineered to secrete interleukin-2 or gamma interferon. Cancer Gene Ther 4, 33–41.PubMedGoogle Scholar
  176. 176.
    Fearon, E. R., Pardoll, D. M., Itaya, T., Golumbek, P., Levitsky, H. I., Simons, J. W., Karasuyama, H., Vogelstein, B., and Frost, P. (1990) Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell 60, 397–403.PubMedCrossRefGoogle Scholar
  177. 177.
    Maass, G., Schmidt, W., Berger, M., Schilcher, F., Koszik, F., Schneeberger, A., Stingl, G., Birnstiel, M. L., and Schweighoffer, T. (1995) Priming of tumor-specific T cells in the draining lymph nodes after immunization with interleukin 2-secreting tumor cells: three consecutive stages may be required for successful tumor vaccination. Proc Natl Acad Sci U S A 92, 5540–5544.PubMedCrossRefGoogle Scholar
  178. 178.
    Moller, P., Sun, Y., Dorbic, T., Alijagic, S., Makki, A., Jurgovsky, K., Schroff, M., Henz, B. M., Wittig, B., and Schadendorf, D. (1998) Vaccination with IL-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: a clinical phase I study. Br J Cancer 77, 1907–1916.PubMedCrossRefGoogle Scholar
  179. 179.
    Sun, Y., Jurgovsky, K., Moller, P., Alijagic, S., Dorbic, T., Georgieva, J., Wittig, B., and Schadendorf, D. (1998) Vaccination with IL-12 gene-modified autologous melanoma cells: preclinical results and a first clinical phase I study. Gene Ther 5, 481–490.PubMedCrossRefGoogle Scholar
  180. 180.
    Czerniecki, B. J., Cohen, P. A., Faries, M., Xu, S., Roros, J. G., and Bedrosian, I. (2001) Diverse functional activity of CD83+ monocyte-derived dendritic cells and the implications for cancer vaccines. Crit Rev Immunol 21, 157–178.PubMedCrossRefGoogle Scholar
  181. 181.
    De Vries, I. J., Krooshoop, D. J., Scharenborg, N. M., Lesterhuis, W. J., Diepstra, J. H., Van Muijen, G. N., Strijk, S. P., Ruers, T. J., Boerman, O. C., Oyen, W. J., Adema, G. J., Punt, C. J., and Figdor, C. G. (2003) Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. Cancer Res 63, 12–17.PubMedGoogle Scholar
  182. 182.
    Jonuleit, H., Kuhn, U., Muller, G., Steinbrink, K., Paragnik, L., Schmitt, E., Knop, J., and Enk, A. H. (1997) Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol 27, 3135–3142.PubMedCrossRefGoogle Scholar
  183. 183.
    Schuler-Thurner, B., Schultz, E. S., Berger, T. G., Weinlich, G., Ebner, S., Woerl, P., Bender, A., Feuerstein, B., Fritsch, P. O., Romani, N., and Schuler, G. (2002) Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J Exp Med 195, 1279–1288.PubMedCrossRefGoogle Scholar
  184. 184.
    Lapenta, C., Santini, S. M., Spada, M., Donati, S., Urbani, F., Accapezzato, D., Franceschini, D., Andreotti, M., Barnaba, V., and Belardelli, F. (2006) IFN-alpha-conditioned dendritic cells are highly efficient in inducing cross-priming CD8(+) T cells against exogenous viral antigens. Eur J Immunol 36, 2046–2060.PubMedCrossRefGoogle Scholar
  185. 185.
    Mosca, P. J., Hobeika, A. C., Clay, T. M., Nair, S. K., Thomas, E. K., Morse, M. A., and Lyerly, H. K. (2000) A subset of human monocyte-derived dendritic cells expresses high levels of interleukin-12 in response to combined CD40 ligand and interferon-gamma treatment. Blood 96, 3499–3504.PubMedGoogle Scholar
  186. 186.
    Czerniecki, B. J., Koski, G. K., Koldovsky, U., Xu, S., Cohen, P. A., Mick, R., Nisenbaum, H., Pasha, T., Xu, M., Fox, K. R., Weinstein, S., Orel, S. G., Vonderheide, R., Coukos, G., DeMichele, A., Araujo, L., Spitz, F. R., Rosen, M., Levine, B. L., June, C., and Zhang, P. J. (2007) Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res 67, 1842–1852.PubMedCrossRefGoogle Scholar
  187. 187.
    Mailliard, R. B., Wankowicz-Kalinska, A., Cai, Q., Wesa, A., Hilkens, C. M., Kapsenberg, M. L., Kirkwood, J. M., Storkus, W. J., and Kalinski, P. (2004) alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. Cancer Res 64, 5934–5937.PubMedCrossRefGoogle Scholar
  188. 188.
    Nair, S., McLaughlin, C., Weizer, A., Su, Z., Boczkowski, D., Dannull, J., Vieweg, J., and Gilboa, E. (2003) Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation. J Immunol 171, 6275–6282.PubMedGoogle Scholar
  189. 189.
    MartIn-Fontecha, A., Sebastiani, S., Hopken, U. E., Uguccioni, M., Lipp, M., Lanzavecchia, A., and Sallusto, F. (2003) Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med 198, 615–621.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Fatma V. Okur
    • Malcolm K. Brenner
      1. 1.Baylor College of MedicineMethodist Hospital and Texas Children–s HospitalHoustonUSA

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