Immunomodulating antibodies and drugs for the treatment of hematological malignancies


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.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.


  1. 1.

    Zou, W. (2005). Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Reviews. Cancer, 5, 263–274.

  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.

  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.

  4. 4.

    Boyiadzis, M., & Foon, K. A. (2008). Approved monoclonal antibodies for cancer therapy. Expert Opinion on Biological Therapy, 8, 1151–1158.

  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.

  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.

  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.

  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.

  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.

  11. 11.

    Zou, W. (2006). Regulatory T cells, tumour immunity and immunotherapy. Nature Reviews. Immunology, 6, 295–307.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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).

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  63. 63.

    Treon, S. P., Soumerai, J. D., Branagan, A. R., et al. (2008). Thalidomide and rituximab in Waldenstrom macroglobulinemia. Blood, 112, 4452–4457.

  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.

  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.

  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.

  67. 67.

    Wiernik, P. H. (2009). Treatment of hematologic neoplasms with new immunomodulatory drugs (IMiDs). Current Treatment Options in Oncology, 10, 1–15.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  111. 111.

    Leach, D. R., Krummel, M. F., & Allison, J. P. (1996). Enhancement of antitumor immunity by CTLA-4 blockade. Science, 271, 1734–1736.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  120. 120.

    Ferrajoli, A. (2009). Incorporating the use of GM-CSF in the treatment of chronic lymphocytic leukemia. Leukaemia & Lymphoma, 50, 514–516.

Download references

Author information

Correspondence to Ronald Levy.

Additional information

Roch Houot and Holbrook Kohrt contributed equally to this study.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Houot, R., Kohrt, H., Goldstein, M.J. et al. Immunomodulating antibodies and drugs for the treatment of hematological malignancies. Cancer Metastasis Rev 30, 97–109 (2011) doi:10.1007/s10555-011-9274-3

Download citation


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