Cancer and Metastasis Reviews

, Volume 30, Issue 1, pp 97–109

Immunomodulating antibodies and drugs for the treatment of hematological malignancies

  • Roch Houot
  • Holbrook Kohrt
  • Matthew J. Goldstein
  • Ronald Levy


The aim of cancer immunotherapy is to induce immune cells to kill tumor and promote immunological memory that protects against tumor recurrence. Most current immunotherapies, such as monoclonal antibodies (mAb), target the tumor cells directly. Advances in our understanding of the immune system such as the role of co-stimulatory and co-inhibitory receptors, and the advent of new immunomodulatory agents provide new opportunities to target the immune system and enhance anti-tumor immune responses. These promising agents include immunomodulating mAbs, Toll-like receptor agonists, IMiDs, and cytokines. In this review, we discuss the current results of immunomodulating agents in the treatment of hematological malignancies and propose applications that include targeting of the innate and adaptive immune systems as well as combinations with tumor-specific mAbs.


Immunomodulation Immunotherapy Monoclonal antibodies Cytokine CpG Thalidomide Lenalidomide Cancer Hematological malignancies Lymphoma Leukemia Myeloma 


  1. 1.
    Zou, W. (2005). Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Reviews. Cancer, 5, 263–274.PubMedCrossRefGoogle Scholar
  2. 2.
    Cartron, G., Watier, H., Golay, J., & Solal-Celigny, P. (2004). From the bench to the bedside: Ways to improve rituximab efficacy. Blood, 104, 2635–2642.PubMedCrossRefGoogle Scholar
  3. 3.
    Coiffier, B., Lepage, E., Briere, J., et al. (2002). CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. The New England Journal of Medicine, 346, 235–242.PubMedCrossRefGoogle Scholar
  4. 4.
    Boyiadzis, M., & Foon, K. A. (2008). Approved monoclonal antibodies for cancer therapy. Expert Opinion on Biological Therapy, 8, 1151–1158.PubMedCrossRefGoogle Scholar
  5. 5.
    Melero, I., Hervas-Stubbs, S., Glennie, M., Pardoll, D. M., & Chen, L. (2007). Immunostimulatory monoclonal antibodies for cancer therapy. Nature Reviews. Cancer, 7, 95–106.PubMedCrossRefGoogle Scholar
  6. 6.
    Suntharalingam, G., Perry, M. R., Ward, S., et al. (2006). Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. The New England Journal of Medicine, 355, 1018–1028.PubMedCrossRefGoogle Scholar
  7. 7.
    Uno, T., Takeda, K., Kojima, Y., et al. (2006). Eradication of established tumors in mice by a combination antibody-based therapy. Natural Medicines, 12, 693–698.CrossRefGoogle Scholar
  8. 8.
    Kohrt, H. E., Houot, R., Goldstein, M. J., Weiskopf, K., Alizadeh, A. A., Brody, J., et al. (2010) CD137 stimulation enhances the anti-lymphoma activity of anti-CD20 antibodies. Blood, doi:10.1182/blood-2010-08-301945.
  9. 9.
    Srivastava, S., Feng, H., Zhang, S., Liang, J., Squiban, P., Farag, S. (2009) Enhancing natural 651 killer (NK) cell mediated killing of non-Hodgkin’s lymphoma. ASH Annual Meeting Abstracts, 114, 2706.Google Scholar
  10. 10.
    Egen, J. G., Kuhns, M. S., & Allison, J. P. (2002). CTLA-4: New insights into its biological function and use in tumor immunotherapy. Nature Immunology, 3, 611–618.PubMedCrossRefGoogle Scholar
  11. 11.
    Zou, W. (2006). Regulatory T cells, tumour immunity and immunotherapy. Nature Reviews. Immunology, 6, 295–307.PubMedCrossRefGoogle Scholar
  12. 12.
    Hodi, F. S., O’Day, S. J., McDermott, D. F., et al. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine, 363, 711–723.PubMedCrossRefGoogle Scholar
  13. 13.
    Chen, L. (2004). Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nature Reviews. Immunology, 4, 336–347.PubMedCrossRefGoogle Scholar
  14. 14.
    Brown, J. A., Dorfman, D. M., Ma, F. R., et al. (2003). Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. Journal of Immunology, 170, 1257–1266.Google Scholar
  15. 15.
    Salih, H. R., Wintterle, S., Krusch, M., et al. (2006). The role of leukemia-derived B7-H1 (PD-L1) in tumor–T-cell interactions in humans. Experimental Hematology, 34, 888–894.PubMedCrossRefGoogle Scholar
  16. 16.
    Xerri, L., Chetaille, B., Seriari, N., et al. (2008). Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Human Pathology, 39, 1050–1058.PubMedCrossRefGoogle Scholar
  17. 17.
    Tamura, H., Dan, K., Tamada, K., et al. (2005). Expression of functional B7-H2 and B7.2 costimulatory molecules and their prognostic implications in de novo acute myeloid leukemia. Clinical Cancer Research, 11, 5708–5717.PubMedCrossRefGoogle Scholar
  18. 18.
    Chen, X., Liu, S., Wang, L., Zhang, W., Ji, Y., & Ma, X. (2008). Clinical significance of B7-H1 (PD-L1) expression in human acute leukemia. Cancer Biology & Therapy, 7, 622–627.CrossRefGoogle Scholar
  19. 19.
    Iwai, Y., Ishida, M., Tanaka, Y., Okazaki, T., Honjo, T., & Minato, N. (2002). Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proceedings of the National Academy of Sciences of the United States of America, 99, 12293–12297.PubMedCrossRefGoogle Scholar
  20. 20.
    Blank, C., Brown, I., Peterson, A. C., et al. (2004). PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Research, 64, 1140–1145.PubMedCrossRefGoogle Scholar
  21. 21.
    Strome, S. E., Dong, H., Tamura, H., et al. (2003). B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Research, 63, 6501–6505.PubMedGoogle Scholar
  22. 22.
    Hardy, B., Kovjazin, R., Raiter, A., Ganor, N., & Novogrodsky, A. (1997). A lymphocyte-activating monoclonal antibody induces regression of human tumors in severe combined immunodeficient mice. Proceedings of the National Academy of Sciences of the United States of America, 94, 5756–5760.PubMedCrossRefGoogle Scholar
  23. 23.
    Hardy, B., Yampolski, I., Kovjazin, R., Galli, M., & Novogrodsky, A. (1994). A monoclonal antibody against a human B lymphoblastoid cell line induces tumor regression in mice. Cancer Research, 54, 5793–5796.PubMedGoogle Scholar
  24. 24.
    Berger, R., Rotem-Yehudar, R., Slama, G., et al. (2008). Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clinical Cancer Research, 14, 3044–3051.PubMedCrossRefGoogle Scholar
  25. 25.
    Westin, J. R., Chu, F., Foglietta, M., Rotem-Yehudar, R., & Neelapu, S. S. (2010). Phase II safety and efficacy study of CT-011, a humanized anti-PD-1 monoclonal antibody, in combination with rituximab in patients with relapsed follicular lymphoma. Journal of Clinical Oncology, 28, 15s.Google Scholar
  26. 26.
    Brahmer, J. R., Drake, C. G., Wollner, I., et al. (2010). Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates. Journal of Clinical Oncology, 28(19), 3167–3175.PubMedCrossRefGoogle Scholar
  27. 27.
    Quezada, S. A., Jarvinen, L. Z., Lind, E. F., & Noelle, R. J. (2004). CD40/CD154 interactions at the interface of tolerance and immunity. Annual Review of Immunology, 22, 307–328.PubMedCrossRefGoogle Scholar
  28. 28.
    Gruss, H. J., & Dower, S. K. (1995). Tumor necrosis factor ligand superfamily: Involvement in the pathology of malignant lymphomas. Blood, 85, 3378–3404.PubMedGoogle Scholar
  29. 29.
    Gruss, H. J., Herrmann, F., Gattei, V., Gloghini, A., Pinto, A., & Carbone, A. (1997). CD40/CD40 ligand interactions in normal, reactive and malignant lympho-hematopoietic tissues. Leukaemia & Lymphoma, 24, 393–422.CrossRefGoogle Scholar
  30. 30.
    Uckun, F. M., Gajl-Peczalska, K., Myers, D. E., Jaszcz, W., Haissig, S., & Ledbetter, J. A. (1990). Temporal association of CD40 antigen expression with discrete stages of human B-cell ontogeny and the efficacy of anti-CD40 immunotoxins against clonogenic B-lineage acute lymphoblastic leukemia as well as B-lineage non-Hodgkin’s lymphoma cells. Blood, 76, 2449–2456.PubMedGoogle Scholar
  31. 31.
    Cella, M., Scheidegger, D., Palmer-Lehmann, K., Lane, P., Lanzavecchia, A., & Alber, G. (1996). Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. The Journal of Experimental Medicine, 184, 747–752.PubMedCrossRefGoogle Scholar
  32. 32.
    Vonderheide, R. H., Flaherty, K. T., Khalil, M., et al. (2007). Clinical activity and immune modulation in cancer patients treated with CP-870, 893, a novel CD40 agonist monoclonal antibody. Journal of Clinical Oncology, 25, 876–883.PubMedCrossRefGoogle Scholar
  33. 33.
    Advani, R., Forero-Torres, A., Furman, R. R., et al. (2009). Phase I study of the humanized antiCD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin’s lymphoma. Journal of Clinical Oncology, 27, 4371–4377.PubMedCrossRefGoogle Scholar
  34. 34.
    Furman, R. R., Forero-Torres, A., Shustov, A., & Drachman, J. G. (2010). A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia. Leukemia and Lymphoma, 51, 228–235.PubMedCrossRefGoogle Scholar
  35. 35.
    Hussein, M., Berenson, J. R., Niesvizky, R., et al. (2010). A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica, 95, 845–848.PubMedCrossRefGoogle Scholar
  36. 36.
    Luqman, M., Klabunde, S., Lin, K., et al. (2008). The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells. Blood, 112, 711–720.PubMedCrossRefGoogle Scholar
  37. 37.
    Byrd, J., Flinn, I., Khan, K., et al. (2006). Pharmacokinetics and pharmacodynamics from a firstin-human phase 1 dose escalation study with antagonist anti-CD40 antibody, HCD122 (formerly CHIR-12.12), in patients with relapsed and refractory Chronic Lymphocytic Leukemia. Blood, 108; abstract 3575.Google Scholar
  38. 38.
    Bensinger, W., Jagannath, S., Becker, P., et al. (2006). A phase 1 dose escalation study of a fully human, antagonist anti-CD40 antibody, HCD122 (formerly CHIR-12.12), in patients with relapsed and refractory multiple myeloma. Blood, 108; abstract 3575.Google Scholar
  39. 39.
    Melero, I., Shuford, W. W., Newby, S. A., et al. (1997). Monoclonal antibodies against the 4-1BB Tcell activation molecule eradicate established tumors. Natural Medicines, 3, 682–685.CrossRefGoogle Scholar
  40. 40.
    Narazaki, H., Zhu, Y., Luo, L., Zhu, G., & Chen, L. (2010). CD137 agonist antibody prevents cancer recurrence: Contribution of CD137 on both hematopoietic and non-hematopoietic cells. Blood, 115(10), 1941–1948.PubMedCrossRefGoogle Scholar
  41. 41.
    Melero, I., Johnston, J. V., Shufford, W. W., Mittler, R. S., & Chen, L. (1998). NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cellular Immunology, 190, 167–172.PubMedCrossRefGoogle Scholar
  42. 42.
    Wilcox, R. A., Chapoval, A. I., Gorski, K. S., et al. (2002). Cutting edge: Expression of functional CD137 receptor by dendritic cells. Journal of Immunology, 168, 4262–4267.Google Scholar
  43. 43.
    Sznol, M., Hodi, F. S., Margolin, K., et al. (2008) Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA). J Clin Oncol.;26 (2008 ASCO Annual Meeting).Google Scholar
  44. 44.
    Houot, R., Goldstein, M. J., Kohrt, H. E., et al. (2009). Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion. Blood, 114, 3431–3438.PubMedCrossRefGoogle Scholar
  45. 45.
    Murillo, O., Arina, A., Hervas-Stubbs, S., et al. (2008). Therapeutic antitumor efficacy of antiCD137 agonistic monoclonal antibody in mouse models of myeloma. Clinical Cancer Research, 14, 6895–6906.PubMedCrossRefGoogle Scholar
  46. 46.
    Goebeler, M., Viardot, A., Noppeney, R., et al. (2010). CD3/CD19 bispecific BiTE antibody blinatumomab treatment of non-Hodgkin lymphoma (NHL) patients: 60 μg/m2/d by continuous infusion is tolerable and results in durable responses. Heamatologica, 95(s2), 230.Google Scholar
  47. 47.
    Bargou, R., Leo, E., Zugmaier, G., et al. (2008). Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science, 321, 974–977.PubMedCrossRefGoogle Scholar
  48. 48.
    Topp, M. S., Zugmaier, G., Goekbuget, N., et al. (2009). Report of a phase II trial of single-agent BiTE® antibody Blinatumomab in patients with minimal residual disease (MRD) positive Bprecursor acute lymphoblastic leukemia (ALL). Blood, 114: abstract 840.Google Scholar
  49. 49.
    Link, B. K., Ballas, Z. K., Weisdorf, D., et al. (2006). Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. Journal of Immunotherapy, 29, 558–568.PubMedCrossRefGoogle Scholar
  50. 50.
    Decker, T., Schneller, F., Sparwasser, T., et al. (2000). Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells. Blood, 95, 999–1006.PubMedGoogle Scholar
  51. 51.
    Jahrsdorfer, B., Hartmann, G., Racila, E., et al. (2001). CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens. Journal of Leukocyte Biology, 69, 81–88.PubMedGoogle Scholar
  52. 52.
    Moga, E., Alvarez, E., Canto, E., et al. (2008). NK cells stimulated with IL-15 or CpG ODN enhance rituximab-dependent cellular cytotoxicity against B-cell lymphoma. Experimental Hematology, 36, 69–77.PubMedCrossRefGoogle Scholar
  53. 53.
    Friedberg, J. W., Kim, H., McCauley, M., et al. (2005). Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: Increased interferon-alpha/beta-inducible gene expression, without significant toxicity. Blood, 105, 489–495.PubMedCrossRefGoogle Scholar
  54. 54.
    Leonard, J. P., Link, B. K., Emmanouilides, C., et al. (2007). Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non-Hodgkin’s lymphoma. Clinical Cancer Research, 13, 6168–6174.PubMedCrossRefGoogle Scholar
  55. 55.
    Friedberg, J. W., Kelly, J. L., Neuberg, D., et al. (2009). Phase II study of a TLR-9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma. British Journal Haematology, 146, 282–291.CrossRefGoogle Scholar
  56. 56.
    Brody, J. D., Ai, W. Z., Czerwinski, D. K., et al. (2010). In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: A phase I/II Study. Journal of Clinical Oncology, 28(28), 4324–4332.PubMedCrossRefGoogle Scholar
  57. 57.
    Li, J., Song, W., Czerwinski, D. K., et al. (2007). Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself. Journal of Immunology, 179, 2493–2500.Google Scholar
  58. 58.
    Singhal, S., Mehta, J., Desikan, R., et al. (1999). Antitumor activity of thalidomide in refractory multiple myeloma. The New England Journal of Medicine, 341, 1565–1571.PubMedCrossRefGoogle Scholar
  59. 59.
    Dimopoulos, M., Spencer, A., Attal, M., et al. (2007). Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. The New England Journal of Medicine, 357, 2123–2132.PubMedCrossRefGoogle Scholar
  60. 60.
    Weber, D. M., Chen, C., Niesvizky, R., et al. (2007). Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. The New England Journal of Medicine, 357, 2133–2142.PubMedCrossRefGoogle Scholar
  61. 61.
    Smith, S. M., Grinblatt, D., Johnson, J. L., et al. (2008). Thalidomide has limited single-agent activity in relapsed or refractory indolent non-Hodgkin lymphomas: A phase II trial of the cancer and leukemia group B. British Journal Haematology, 140, 313–319.CrossRefGoogle Scholar
  62. 62.
    Kaufmann, H., Raderer, M., Wohrer, S., et al. (2004). Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood, 104, 2269–2271.PubMedCrossRefGoogle Scholar
  63. 63.
    Treon, S. P., Soumerai, J. D., Branagan, A. R., et al. (2008). Thalidomide and rituximab in Waldenstrom macroglobulinemia. Blood, 112, 4452–4457.PubMedCrossRefGoogle Scholar
  64. 64.
    Chanan-Khan, A., Miller, K. C., Musial, L., et al. (2006). Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: Results of a phase II study. Journal of Clinical Oncology, 24, 5343–5349.PubMedCrossRefGoogle Scholar
  65. 65.
    Ferrajoli, A., Lee, B. N., Schlette, E. J., et al. (2008). Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood, 111, 5291–5297.PubMedCrossRefGoogle Scholar
  66. 66.
    List, A., Dewald, G., Bennett, J., et al. (2006). Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. The New England Journal of Medicine, 355, 1456–1465.PubMedCrossRefGoogle Scholar
  67. 67.
    Wiernik, P. H. (2009). Treatment of hematologic neoplasms with new immunomodulatory drugs (IMiDs). Current Treatment Options in Oncology, 10, 1–15.PubMedCrossRefGoogle Scholar
  68. 68.
    Witzig, T. E., Wiernik, P. H., Moore, T., et al. (2009). Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s lymphoma. Journal of Clinical Oncology, 27, 5404–5409.PubMedCrossRefGoogle Scholar
  69. 69.
    Habermann, T. M., Lossos, I. S., Justice, G., et al. (2009). Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. British Journal Haematology, 145, 344–349.CrossRefGoogle Scholar
  70. 70.
    Ebert, B. L., Galili, N., Tamayo, P., et al. (2008). An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome. PLoS Medicine, 5, e35.PubMedCrossRefGoogle Scholar
  71. 71.
    Andritsos, L. A., Johnson, A. J., Lozanski, G., et al. (2008). Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. Journal of Clinical Oncology, 26, 2519–2525.PubMedCrossRefGoogle Scholar
  72. 72.
    Boll, B., Borchmann, P., Topp, M. S., et al. (2010). Lenalidomide in patients with refractory or multiple relapsed Hodgkin lymphoma. British Journal of Haematology, 148, 480–482.PubMedCrossRefGoogle Scholar
  73. 73.
    Corazzelli, G., De Filippi, R., Capobianco, G., et al. (2009). Tumor flare reactions and response to lenalidomide in patients with refractory classic Hodgkin lymphoma. American Journal of Hematology, 85, 87–90.Google Scholar
  74. 74.
    Dueck, G., Chua, N., Prasad, A., et al. (2010). Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma. Cancer, 116(19), 4541–4548.PubMedCrossRefGoogle Scholar
  75. 75.
    Wu, L., Adams, M., Carter, T., et al. (2008). lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clinical Cancer Research, 14, 4650–4657.PubMedCrossRefGoogle Scholar
  76. 76.
    Lapalombella, R., Yu, B., Triantafillou, G., et al. (2008). Lenalidomide down-regulates the CD20 antigen and antagonizes direct and antibody-dependent cellular cytotoxicity of rituximab on primary chronic lymphocytic leukemia cells. Blood, 112, 5180–5189.PubMedCrossRefGoogle Scholar
  77. 77.
    Hernandez-Ilizaliturri, F. J., Reddy, N., Holkova, B., Ottman, E., & Czuczman, M. S. (2005). Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clinical Cancer Research, 11, 59845992.CrossRefGoogle Scholar
  78. 78.
    Treon, S. P., Soumerai, J. D., Branagan, A. R., et al. (2009). Lenalidomide and rituximab in Waldenstrom’s macroglobulinemia. Clinical Cancer Research, 15, 355–360.PubMedCrossRefGoogle Scholar
  79. 79.
    Wang, L., Fayad, L., Hagemeister, F. B., et al. (2009). A Phase I/II study of lenalidomide in combination with rituximab in relapsed/refractory mantle cell lymphoma. ASH meeting, Abstr 2719.Google Scholar
  80. 80.
    Dutia, M., DeRoock, I., Chee, K., et al. (2010). Analysis of a phase 2 study of lenalidomide and rituximab in relapsed or refractory non-Hodgkin’s lymphoma. EHA meeting, abst # 0295.Google Scholar
  81. 81.
    Fowler, N. H., McLaughlin, P., Hagemeister, F. B., et al. (2010). Complete response rates with lenalidomide plus rituximab for untreated indolent B-cell non-hodgkin’s lymphoma. Journal of Clinical Oncology, 28, 15s.Google Scholar
  82. 82.
    Plosker, G. L., & Figgitt, D. P. (2003). Rituximab: A review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs, 63, 803–843.PubMedCrossRefGoogle Scholar
  83. 83.
    McLaughlin, P., Grillo-Lopez, A. J., Link, B. K., et al. (1998). Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. Journal of Clinical Oncology, 16, 2825–2833.PubMedGoogle Scholar
  84. 84.
    Rosenberg, S. A., Lotze, M. T., Muul, L. M., et al. (1987). A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. The New England Journal of Medicine, 316, 889–897.PubMedCrossRefGoogle Scholar
  85. 85.
    Eisenbeis, C. F., Grainger, A., Fischer, B., et al. (2004). Combination immunotherapy of B-cell non-Hodgkin’s lymphoma with rituximab and interleukin-2: A preclinical and phase I study. Clinical Cancer Research, 10, 6101–6110.PubMedCrossRefGoogle Scholar
  86. 86.
    Friedberg, J. W., Neuberg, D., Gribben, J. G., et al. (2002). Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin’s lymphoma. British Journal Haematology, 117, 828–834.CrossRefGoogle Scholar
  87. 87.
    Gluck, W. L., Hurst, D., Yuen, A., et al. (2004). Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-Hodgkin’s lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response. Clinical Cancer Research, 10, 2253–2264.PubMedCrossRefGoogle Scholar
  88. 88.
    Khan, K. D., Emmanouilides, C., Benson, D. M., Jr., et al. (2006). A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin’s lymphoma. Clinical Cancer Research, 12, 7046–7053.PubMedCrossRefGoogle Scholar
  89. 89.
    Banks, R. E., Patel, P. M., & Selby, P. J. (1995). Interleukin 12: A new clinical player in cytokine therapy. British Journal of Cancer, 71, 655–659.PubMedCrossRefGoogle Scholar
  90. 90.
    Younes, A., Pro, B., Robertson, M. J., et al. (2004). Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin’s lymphoma and Hodgkin’s disease. Clinical Cancer Research, 10, 5432–5438.PubMedCrossRefGoogle Scholar
  91. 91.
    Ansell, S. M., Geyer, S. M., Maurer, M. J., et al. (2006). Randomized phase II study of interleukin-12 in combination with rituximab in previously treated non-Hodgkin’s lymphoma patients. Clinical Cancer Research, 12, 6056–6063.PubMedCrossRefGoogle Scholar
  92. 92.
    Andorsky, D. J., & Timmerman, J. M. (2008). Interleukin-21: Biology and application to cancer therapy. Expert Opinion on Biological Therapy, 8, 1295–1307.PubMedCrossRefGoogle Scholar
  93. 93.
    Roda, J. M., Joshi, T., Butchar, J. P., et al. (2007). The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. Clinical Cancer Research, 13, 6419–6428.PubMedCrossRefGoogle Scholar
  94. 94.
    VanderMolen, L. A., Steis, R. G., Duffey, P. L., et al. (1990). Low-versus high-dose interferon alfa-2a in relapsed indolent non-Hodgkin’s lymphoma. Journal of the National Cancer Institute, 82, 235–238.PubMedCrossRefGoogle Scholar
  95. 95.
    Sacchi, S., Federico, M., Vitolo, U., et al. (2001). Clinical activity and safety of combination immunotherapy with IFN-alpha 2a and rituximab in patients with relapsed low grade non-Hodgkin’s lymphoma. Haematologica, 86, 951–958.PubMedGoogle Scholar
  96. 96.
    Davis, T. A., Maloney, D. G., Grillo-Lopez, A. J., et al. (2000). Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma with rituximab and interferon-alpha-2a. Clinical Cancer Research, 6, 2644–2652.PubMedGoogle Scholar
  97. 97.
    Kimby, E., Jurlander, J., Geisler, C., et al. (2008). Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: A randomized phase II study from the Nordic Lymphoma Group. Leukaemia & Lymphoma, 49, 102–112.CrossRefGoogle Scholar
  98. 98.
    van der Kolk, L. E., Grillo-Lopez, A. J., Baars, J. W., & van Oers, M. H. (2003). Treatment of relapsed Bcell non-Hodgkin’s lymphoma with a combination of chimeric anti-CD20 monoclonal antibodies (rituximab) and G-CSF: Final report on safety and efficacy. Leukemia, 17, 1658–1664.PubMedCrossRefGoogle Scholar
  99. 99.
    Cartron, G., Zhao-Yang, L., Baudard, M., et al. (2008). Granulocyte-macrophage colonystimulating factor potentiates rituximab in patients with relapsed follicular lymphoma: Results of a phase II study. Journal of Clinical Oncology, 26, 2725–2731.PubMedCrossRefGoogle Scholar
  100. 100.
    Hainsworth, J. D., Litchy, S., Barton, J. H., et al. (2003). Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network. Journal of Clinical Oncology, 21, 1746–1751.PubMedCrossRefGoogle Scholar
  101. 101.
    Huhn, D., von Schilling, C., Wilhelm, M., et al. (2001). Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood, 98, 1326–1331.PubMedCrossRefGoogle Scholar
  102. 102.
    Itala, M., Geisler, C. H., Kimby, E., et al. (2002). Standard-dose anti-CD20 antibody rituximab has efficacy in chronic lymphocytic leukaemia: Results from a Nordic multicentre study. European Journal of Haematology, 69, 129–134.PubMedCrossRefGoogle Scholar
  103. 103.
    McLaughlin, P., Liu, N., Poindexter, N., et al. (2005). Rituximab plus GM-CSF (Leukine) for indolent lymphoma. Proceedings of the 9th International Conference on Malignant lymphomas. Annals of Oncology, 16, v68.CrossRefGoogle Scholar
  104. 104.
    Kjaergaard, J., Tanaka, J., Kim, J. A., Rothchild, K., Weinberg, A., & Shu, S. (2000). Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth. Cancer Research, 60, 5514–5521.PubMedGoogle Scholar
  105. 105.
    Piconese, S., Valzasina, B., & Colombo, M. P. (2008). OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. The Journal of Experimental Medicine, 205, 825–839.PubMedCrossRefGoogle Scholar
  106. 106.
    Weinberg, A. D., Rivera, M. M., Prell, R., et al. (2000). Engagement of the OX-40 receptor in vivo enhances antitumor immunity. Journal of Immunology, 164, 2160–2169.Google Scholar
  107. 107.
    Ko, K., Yamazaki, S., Nakamura, K., et al. (2005). Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. The Journal of Experimental Medicine, 202, 885–891.PubMedCrossRefGoogle Scholar
  108. 108.
    French, R. R., Taraban, V. Y., Crowther, G. R., et al. (2007). Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation. Blood, 109, 4810–4815.PubMedCrossRefGoogle Scholar
  109. 109.
    Sakanishi, T., & Yagita, H. (2010). Anti-tumor effects of depleting and non-depleting anti-CD27 monoclonal antibodies in immune-competent mice. Biochemical and Biophysical Research Communications, 393, 829–835.PubMedCrossRefGoogle Scholar
  110. 110.
    Kwon, E. D., Hurwitz, A. A., Foster, B. A., et al. (1997). Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 94, 8099–8103.PubMedCrossRefGoogle Scholar
  111. 111.
    Leach, D. R., Krummel, M. F., & Allison, J. P. (1996). Enhancement of antitumor immunity by CTLA-4 blockade. Science, 271, 1734–1736.PubMedCrossRefGoogle Scholar
  112. 112.
    Hirano, F., Kaneko, K., Tamura, H., et al. (2005). Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Research, 65, 1089–1096.PubMedGoogle Scholar
  113. 113.
    French, R. R., Chan, H. T., Tutt, A. L., & Glennie, M. J. (1999). CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Natural Medicines, 5, 548–553.CrossRefGoogle Scholar
  114. 114.
    Law, C. L., Gordon, K. A., Collier, J., et al. (2005). Preclinical antilymphoma activity of a humanized anti-CD40 monoclonal antibody, SGN-40. Cancer Research, 65, 8331–8338.PubMedCrossRefGoogle Scholar
  115. 115.
    Romagne, F., Andre, P., Spee, P., et al. (2009). Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood, 114, 2667–2677.PubMedGoogle Scholar
  116. 116.
    O’Mahony, D., Morris, J. C., Quinn, C., et al. (2007). A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clinical Cancer Research, 13, 958–964.PubMedCrossRefGoogle Scholar
  117. 117.
    Bashey, A., Medina, B., Corringham, S., et al. (2009). CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood, 113, 1581–1588.PubMedCrossRefGoogle Scholar
  118. 118.
    Ansell, S. M., Hurvitz, S. A., Koenig, P. A., et al. (2009). Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clinical Cancer Research, 15, 6446–6453.PubMedCrossRefGoogle Scholar
  119. 119.
    Ansell, S. M., Witzig, T. E., Kurtin, P. J., et al. (2002). Phase 1 study of interleukin-12 in combination with rituximab in patients with B-cell non-Hodgkin lymphoma. Blood, 99, 67–74.PubMedCrossRefGoogle Scholar
  120. 120.
    Ferrajoli, A. (2009). Incorporating the use of GM-CSF in the treatment of chronic lymphocytic leukemia. Leukaemia & Lymphoma, 50, 514–516.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Roch Houot
    • 1
  • Holbrook Kohrt
    • 2
  • Matthew J. Goldstein
    • 2
  • Ronald Levy
    • 2
  1. 1.Service d’Hématologie Clinique & INSERM U917Centre Hospitalier Universitaire de RennesRennesFrance
  2. 2.Department of Medicine, Division of OncologyStanford UniversityStanfordUSA

Personalised recommendations