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Clinical and Developmental Immunology
Volume 2012, Article ID 196063, 13 pages
http://dx.doi.org/10.1155/2012/196063
Review Article

Targeting Multiple-Myeloma-Induced Immune Dysfunction to Improve Immunotherapy Outcomes

1Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesù Children’s Hospital, Piazza Sant’Onofrio 4, 00165 Rome, Italy
2Catholic University Medical School, 00168 Rome, Italy
3University of Pavia, 27100 Pavia, Italy

Received 30 October 2011; Revised 12 January 2012; Accepted 29 January 2012

Academic Editor: Arnon Nagler

Copyright © 2012 Sergio Rutella and Franco Locatelli. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. Palumbo and K. Anderson, “Multiple myeloma,” New England Journal of Medicine, vol. 364, no. 11, pp. 1046–1060, 2011. View at Google Scholar
  2. J. Bladé, L. Rosiñol, M. T. Cibeira, M. Rovira, and E. Carreras, “Hematopoietic stem cell transplantation for multiple myeloma beyond 2010,” Blood, vol. 115, no. 18, pp. 3655–3663, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. C. Roddie and K. S. Peggs, “Donor lymphocyte infusion following allogeneic hematopoietic stem cell transplantation,” Expert Opinion on Biological Therapy, vol. 11, no. 4, pp. 473–487, 2011. View at Publisher · View at Google Scholar
  4. B. Björkstrand, S. Iacobelli, U. Hegenbart et al., “Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up,” Journal of Clinical Oncology, vol. 29, no. 22, pp. 3016–3022, 2011. View at Publisher · View at Google Scholar
  5. A. Krishnan, M. C. Pasquini, B. Logan et al., “Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial,” The Lancet Oncology, vol. 12, no. 13, pp. 1195–1203, 2011. View at Publisher · View at Google Scholar
  6. O. Ringden, S. Shrestha, G. T. da Silva et al., “Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma,” Bone Marrow Transplantation. In press.
  7. C. Crawley, R. Szydlo, M. Lalancette et al., “Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT,” Blood, vol. 106, no. 9, pp. 2969–2976, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. P. A. Holloway, N. Kaldenhoven, M. van Dijk et al., “Susceptibility of malignant plasma cells to HA-1H specific lysis suggests a role for the minor histocompatibility antigen HA-1 in the graft-versus-myeloma effect,” Leukemia, vol. 18, no. 9, pp. 1543–1545, 2004. View at Publisher · View at Google Scholar · View at Scopus
  9. N. Kröger, A. Shimoni, M. Zagrivnaja et al., “Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma,” Blood, vol. 104, no. 10, pp. 3361–3363, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. N. Van Baren, F. Brasseur, D. Godelaine et al., “Genes encoding tumor-specific antigens are expressed in human myeloma cells,” Blood, vol. 94, no. 4, pp. 1156–1164, 1999. View at Google Scholar · View at Scopus
  11. D. Atanackovic, J. Arfsten, Y. Cao et al., “Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation,” Blood, vol. 109, no. 3, pp. 1103–1112, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. F. Van Rhee, S. M. Szmania, F. Zhan et al., “NY-ESO-1 is highly expressed in poor-prognosis multiple myeloma and induces spontaneous humoral and cellular immune responses,” Blood, vol. 105, no. 10, pp. 3939–3944, 2005. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Collins, V. Ling, and B. M. Carreno, “The B7 family of immune-regulatory ligands,” Genome Biology, vol. 6, no. 6, article 223, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. H. Tamura, K. Dan, K. Tamada et al., “Expression of functional B7-H2 and B7.2 costimulatory molecules and their prognostic implications in de novo acute myeloid leukemia,” Clinical Cancer Research, vol. 11, no. 16, pp. 5708–5717, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. Y. Iwai, M. Ishida, Y. Tanaka, T. Okazaki, T. Honjo, and N. Minato, “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, vol. 99, no. 19, pp. 12293–12297, 2002. View at Publisher · View at Google Scholar · View at Scopus
  16. J. Liu, A. Hamrouni, D. Wolowiec et al., “Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-γ and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway,” Blood, vol. 110, no. 1, pp. 296–304, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. K. Kuranda, C. Berthon, C. Dupont et al., “A subpopulation of malignant CD34+CD138+B7-H1+ plasma cells is present in multiple myeloma patients,” Experimental Hematology, vol. 38, no. 2, pp. 124–131, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. L. M. Francisco, V. H. Salinas, K. E. Brown et al., “PD-L1 regulates the development, maintenance, and function of induced regulatory T cells,” Journal of Experimental Medicine, vol. 206, no. 13, pp. 3015–3029, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. T. Fukaya, H. Takagi, Y. Sato et al., “Crucial roles of B7-H1 and B7-DC expressed on mesenteric lymph node dendritic cells in the generation of antigen-specific CD4+Foxp3+ regulatory T cells in the establishment of oral tolerance,” Blood, vol. 116, no. 13, pp. 2266–2276, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. T. Yamashita, H. Tamura, C. Satoh et al., “Functional B7.2 and B7-H2 molecules on myeloma cells are associated with a growth advantage,” Clinical Cancer Research, vol. 15, no. 3, pp. 770–777, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. R. Spisek, A. Kukreja, L. C. Chen et al., “Frequent and specific immunity to the embryonal stem cell-associated antigen SOX2 in patients with monoclonal gammopathy,” Journal of Experimental Medicine, vol. 204, no. 4, pp. 831–840, 2007. View at Publisher · View at Google Scholar · View at Scopus
  22. J. R. Nair, L. M. Carlson, C. Koorella et al., “CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment,” Journal of Immunology, vol. 187, no. 3, pp. 1243–1253, 2011. View at Publisher · View at Google Scholar
  23. T. Hideshima, C. Mitsiades, G. Tonon, P. G. Richardson, and K. C. Anderson, “Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets,” Nature Reviews Cancer, vol. 7, no. 8, pp. 585–598, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. A. C. Sprynski, D. Hose, A. Kassambara et al., “Insulin is a potent myeloma cell growth factor through insulin/IGF-1 hybrid receptor activation,” Leukemia, vol. 24, no. 11, pp. 1940–1950, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. K. Okunishi, M. Dohi, K. Nakagome et al., “A novel role of hepatocyte growth factor as an immune regulator through suppressing dendritic cell function,” Journal of Immunology, vol. 175, no. 7, pp. 4745–4753, 2005. View at Google Scholar · View at Scopus
  26. S. Rutella, G. Bonanno, A. Procoli et al., “Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features,” Blood, vol. 108, no. 1, pp. 218–227, 2006. View at Publisher · View at Google Scholar · View at Scopus
  27. P. Y. Wen, D. Schiff, T. F. Cloughesy et al., “A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma,” Neuro-Oncology, vol. 13, no. 4, pp. 437–446, 2011. View at Publisher · View at Google Scholar
  28. K. J. Kim, L. Wang, Y. C. Su et al., “Systemic anti-hepatocyte growth factor monoclonal antibody therapy induces the regression of intracranial glioma xenografts,” Clinical Cancer Research, vol. 12, no. 4, pp. 1292–1298, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. P. M. Comoglio, S. Giordano, and L. Trusolino, “Drug development of MET inhibitors: targeting oncogene addiction and expedience,” Nature Reviews Drug Discovery, vol. 7, no. 6, pp. 504–516, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. T. Martens, N. O. Schmidt, C. Eckerich et al., “A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo,” Clinical Cancer Research, vol. 12, no. 20, pp. 6144–6152, 2006. View at Publisher · View at Google Scholar · View at Scopus
  31. T. Kikuchi, M. Maemondo, K. Narumi, K. Matsumoto, T. Nakamura, and T. Nukiwa, “Tumor suppression induced by intratumor administration of adenovirus vector expressing NK4, a 4-kringle antagonist of hepatocyte growth factor, and naive dendritic cells,” Blood, vol. 100, no. 12, pp. 3950–3959, 2002. View at Publisher · View at Google Scholar · View at Scopus
  32. W. Du, Y. Hattori, T. Yamada et al., “NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells: molecular targeting of angiogenic growth factor,” Blood, vol. 109, no. 7, pp. 3042–3049, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. G. Somlo, A. Lashkari, W. Bellamy et al., “Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory multiple myeloma: a California Cancer Consortium trial,” British Journal of Haematology, vol. 154, no. 4, pp. 533–535, 2011. View at Publisher · View at Google Scholar
  34. J. Dannull, Z. Su, D. Rizzieri et al., “Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells,” Journal of Clinical Investigation, vol. 115, no. 12, pp. 3623–3633, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. G. Bonanno, M. Corallo, and A. Mariotti, “Indoleamine 2,3-dioxygenase (IDO) is expressed by multiple myeloma plasma cells and promotes the differentiation of regulatory T cells: investigations into the role of hepatocyte growth factor,” Blood, vol. 112, no. 2, p. 1680, 2008. View at Google Scholar
  36. H. H. Soliman, S. J. Antonia, D. Sullivan, N. Vanahanian, and C. Link, “Overcoming tumor antigen anergy in human malignancies using the novel indoleamine 2,3-dioxygenase (IDO) enzyme inhibitor, 1-methyl-D-tryptophan (1MT),” Journal of Clinical Oncology, vol. 27, supplement 15, abstract 3004, 2009. View at Google Scholar
  37. S. Wei, A. B. Shreiner, N. Takeshita, L. Chen, W. Zou, and A. E. Chang, “Tumor-induced immune suppression of in vivo effector T-cell priming is mediated by the B7-H1/PD-1 axis and transforming growth factor β,” Cancer Research, vol. 68, no. 13, pp. 5432–5438, 2008. View at Publisher · View at Google Scholar · View at Scopus
  38. R. D. Brown, B. Pope, A. Murray et al., “Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-β1 and interleukin-10,” Blood, vol. 98, no. 10, pp. 2992–2998, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. J. Rosenblatt, B. Vasir, L. Uhl et al., “Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma,” Blood, vol. 117, no. 2, pp. 393–402, 2011. View at Publisher · View at Google Scholar
  40. Q. Yi, S. Szmania, J. Freeman et al., “Optimizing dendritic cell-based immunotherapy in multiple myeloma: intranodal injections of idiotype-pulsed CD40 ligand-matured vaccines led to induction of type-1 and cytotoxic T-cell immune responses in patients,” British Journal of Haematology, vol. 150, no. 5, pp. 554–564, 2010. View at Publisher · View at Google Scholar · View at Scopus
  41. T. Rasmussen, L. Hansson, A. Österborg, H. E. Johnsen, and H. Mellstedt, “Idiotype vaccination in multiple myeloma induced a reduction of circulating clonal tumor B cells,” Blood, vol. 101, no. 11, pp. 4607–4610, 2003. View at Publisher · View at Google Scholar · View at Scopus
  42. V. L. Reichardt, C. Y. Okada, A. Liso et al., “Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma—a feasibility study,” Blood, vol. 93, no. 7, pp. 2411–2419, 1999. View at Google Scholar · View at Scopus
  43. J. Moreaux, D. Hose, T. Reme et al., “CD200 is a new prognostic factor in multiple myeloma,” Blood, vol. 108, no. 13, pp. 4194–4197, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. R. M. Gorczynski, L. Lee, and I. Boudakov, “Augmented induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R,” Transplantation, vol. 79, no. 9, pp. 1180–1183, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Beyer, M. Kochanek, T. Giese et al., “In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma,” Blood, vol. 107, no. 10, pp. 3940–3949, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. M. K. Brimnes, A. J. Vangsted, L. M. Knudsen et al., “Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DRlow myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma,” Scandinavian Journal of Immunology, vol. 72, no. 6, pp. 540–547, 2010. View at Publisher · View at Google Scholar · View at Scopus
  47. S. Feyler, M. Von Lilienfeld-Toal, S. Jarmin et al., “CD4+CD25+FoxP3+ regulatory T cells are increased whilst CD3+CD4CD8αβTCR+ Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden,” British Journal of Haematology, vol. 144, no. 5, pp. 686–695, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. S. Han, B. Wang, M. J. Cotter et al., “Overcoming immune tolerance against multiple myeloma with lentiviral calnexin-engineered dendritic cells,” Molecular Therapy, vol. 16, no. 2, pp. 269–279, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. R. H. Prabhala, P. Neri, J. E. Bae et al., “Dysfunctional T regulatory cells in multiple myeloma,” Blood, vol. 107, no. 1, pp. 301–304, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. M. Beyer, S. Classen, E. Endl et al., “Comparative approach to define increased regulatory T cells in different cancer subtypes by combined assessment of CD127 and FOXP3,” Clinical and Developmental Immunology, vol. 2011, Article ID 734036, 12 pages, 2011. View at Publisher · View at Google Scholar
  51. D. Atanackovic, Y. Cao, T. Luetkens et al., “CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma following allogeneic stem cell transplantation,” Haematologica, vol. 93, no. 3, pp. 423–430, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. M. C. Minnema, M. S. van der Veer, T. Aarts, M. Emmelot, T. Mutis, and H. M. Lokhorst, “Lenalidomide alone or in combination with dexamethasone is highly effective in patients with relapsed multiple myeloma following allogeneic stem cell transplantation and increases the frequency of CD4+Foxp3+ T cells,” Leukemia, vol. 23, no. 3, pp. 605–607, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. B.-N. Lee, H. Gao, E. N. Cohen et al., “Treatment with lenalidomide modulates T-cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia,” Cancer, vol. 117, no. 17, pp. 3999–4008, 2011. View at Publisher · View at Google Scholar
  54. I. Idler, K. Giannopoulos, T. Zenz et al., “Lenalidomide treatment of chronic lymphocytic leukaemia patients reduces regulatory T cells and induces Th17 T helper cells,” British Journal of Haematology, vol. 148, no. 6, pp. 948–950, 2010. View at Publisher · View at Google Scholar · View at Scopus
  55. S. L. Berg, M. S. Cairo, H. Russell et al., “Safety, pharmacokinetics, and immunomodulatory effects of lenalidomide in children and adolescents with relapsed/refractory solid tumors or myelodysplastic syndrome: a Children's Oncology Group phase I consortium report,” Journal of Clinical Oncology, vol. 29, no. 3, pp. 316–323, 2011. View at Publisher · View at Google Scholar
  56. C. Galustian, B. Meyer, M. C. Labarthe et al., “The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells,” Cancer Immunology, Immunotherapy, vol. 58, no. 7, pp. 1033–1045, 2009. View at Publisher · View at Google Scholar · View at Scopus
  57. K. Giannopoulos, M. Schmitt, P. Własiuk et al., “The high frequency of T regulatory cells in patients with B-cell chronic lymphocytic leukemia is diminished through treatment with thalidomide,” Leukemia, vol. 22, no. 1, pp. 222–224, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. D. Chauhan, H. Uchiyama, Y. Akbarali et al., “Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-κB,” Blood, vol. 87, no. 3, pp. 1104–1112, 1996. View at Google Scholar · View at Scopus
  59. M. Urashima, A. Ogata, D. Chauhan et al., “Transforming growth factor-β1: differential effects on multiple myeloma versus normal B cells,” Blood, vol. 87, no. 5, pp. 1928–1938, 1996. View at Google Scholar · View at Scopus
  60. N. F. Andersen, T. Standal, J. L. Nielsen et al., “Syndecan-1 and angiogenic cytokines in multiple myeloma: correlation with bone marrow angiogenesis and survival,” British Journal of Haematology, vol. 128, no. 2, pp. 210–217, 2005. View at Publisher · View at Google Scholar · View at Scopus
  61. D. Hose, J. Moreaux, T. Meissner et al., “Induction of angiogenesis by normal and malignant plasma cells,” Blood, vol. 114, no. 1, pp. 128–143, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. P. W. B. Derksen, D. J. J. de Gorter, H. P. Meijer et al., “The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma,” Leukemia, vol. 17, no. 4, pp. 764–774, 2003. View at Publisher · View at Google Scholar · View at Scopus
  63. K. F. Wader, U. M. Fagerli, R. U. Holt et al., “Elevated serum concentrations of activated hepatocyte growth factor activator in patients with multiple myeloma,” European Journal of Haematology, vol. 81, no. 5, pp. 380–383, 2008. View at Publisher · View at Google Scholar · View at Scopus
  64. E. P. M. Tjin, P. W. B. Derksen, H. Kataoka, M. Spaargaren, and S. T. Pals, “Multiple myeloma cells catalyze hepatocyte growth factor (HGF) activation by secreting the serine protease HGF-activator,” Blood, vol. 104, no. 7, pp. 2172–2175, 2004. View at Publisher · View at Google Scholar · View at Scopus
  65. M. P. Purdue, Q. Lan, I. Menashe et al., “Variation in innate immunity genes and risk of multiple myeloma,” Hematological Oncology, vol. 29, no. 1, pp. 42–46, 2011. View at Publisher · View at Google Scholar
  66. C. Seidel, M. Børset, I. Turesson, N. Abildgaard, A. Sundan, and A. Waage, “Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma,” Blood, vol. 91, no. 3, pp. 806–812, 1998. View at Google Scholar
  67. P. Ludek, S. Hana, A. Zdenek et al., “Treatment response to bortezomib in multiple myeloma correlates with plasma hepatocyte growth factor concentration and bone marrow thrombospondin concentration,” European Journal of Haematology, vol. 84, no. 4, pp. 332–336, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. L. Pour, H. Svachova, Z. Adam et al., “Pretreatment hepatocyte growth factor and thrombospondin-1 levels predict response to high-dose chemotherapy for multiple myeloma,” Neoplasma, vol. 57, no. 1, pp. 29–34, 2010. View at Google Scholar · View at Scopus
  69. C. Seidel, S. Lenhoff, S. Brabrand et al., “Hepatocyte growth factor in myeloma patients treated with high-dose chemotherapy,” British Journal of Haematology, vol. 119, no. 3, pp. 672–676, 2002. View at Publisher · View at Google Scholar · View at Scopus
  70. T. Kuroiwa, E. Kakishita, T. Hamano et al., “Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function,” Journal of Clinical Investigation, vol. 107, no. 11, pp. 1365–1373, 2001. View at Google Scholar · View at Scopus
  71. C. Uyttenhove, L. Pilotte, I. Théate et al., “Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase,” Nature Medicine, vol. 9, no. 10, pp. 1269–1274, 2003. View at Publisher · View at Google Scholar · View at Scopus
  72. A. Curti, M. Aluigi, S. Pandolfi et al., “Acute myeloid leukemia cells constitutively express the immunoregulatory enzyme indoleamine 2,3-dioxygenase,” Leukemia, vol. 21, no. 2, pp. 353–355, 2007. View at Publisher · View at Google Scholar · View at Scopus
  73. D. H. Munn and A. L. Mellor, “Indoleamine 2,3-dioxygenase and tumor-induced tolerance,” Journal of Clinical Investigation, vol. 117, no. 5, pp. 1147–1154, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. S. Wang, J. Yang, J. Qian, M. Wezeman, L. W. Kwak, and Q. Yi, “Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma,” Blood, vol. 107, no. 6, pp. 2432–2439, 2006. View at Publisher · View at Google Scholar · View at Scopus
  75. S. Rutella, S. Danese, and G. Leone, “Tolerogenic dendritic cells: cytokine modulation comes of age,” Blood, vol. 108, no. 5, pp. 1435–1440, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. R. Brown, A. Murray, B. Pope et al., “Either interleukin-12 or interferon-γ can correct the dendritic cell defect induced by transforming growth factor β1 in patients with myeloma,” British Journal of Haematology, vol. 125, no. 6, pp. 743–748, 2004. View at Publisher · View at Google Scholar · View at Scopus
  77. M. Ratta, F. Fagnoni, A. Curti et al., “Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6,” Blood, vol. 100, no. 1, pp. 230–237, 2002. View at Publisher · View at Google Scholar · View at Scopus
  78. D. K. Banerjee, M. V. Dhodapkar, E. Matayeva, R. M. Steinman, and K. M. Dhodapkar, “Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients,” Blood, vol. 108, no. 8, pp. 2655–2661, 2006. View at Publisher · View at Google Scholar · View at Scopus
  79. R. Berger, R. Rotem-Yehudar, G. Slama et al., “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, vol. 14, no. 10, pp. 3044–3051, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. D. M. Benson Jr., C. E. Bakan, A. Mishra et al., “The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody,” Blood, vol. 116, no. 13, pp. 2286–2294, 2010. View at Publisher · View at Google Scholar · View at Scopus
  81. W. H.D. Hallett, W. Jing, W. R. Drobyski, and B. D. Johnson, “Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade,” Biology of Blood and Marrow Transplantation, vol. 17, no. 8, pp. 1133–1145, 2011. View at Publisher · View at Google Scholar
  82. M. Bouvier, “Accessory proteins and the assembly of human class I MHC molecules: a molecular and structural perspective,” Molecular Immunology, vol. 39, no. 12, pp. 697–706, 2003. View at Publisher · View at Google Scholar · View at Scopus
  83. M. S. Gordon, C. S. Sweeney, D. S. Mendelson et al., “Safety, pharmacokinetics, and pharmacodynamics of AMG 102, a fully human hepatocyte growth factor-neutralizing monoclonal antibody, in a first-in-human study of patients with advanced solid tumors,” Clinical Cancer Research, vol. 16, no. 2, pp. 699–710, 2010. View at Publisher · View at Google Scholar · View at Scopus
  84. P. J. Rosen, C. J. Sweeney, D. J. Park et al., “A phase Ib study of AMG 102 in combination with bevacizumab or motesanib in patients with advanced solid tumors,” Clinical Cancer Research, vol. 16, no. 9, pp. 2677–2687, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. M. G. Iachininoto, E. R. Nuzzolo, and A. Di Maggio, “COX-2 inhibition suppresses the interferon-γ-induced expression of indoleamine 2,3-dioxygenase (IDO) in human leukemia cell lines,” Blood, vol. 112, no. 2, p. 1623, 2008. View at Google Scholar
  86. A. Cesario, B. Rocca, and S. Rutella, “The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 in chronic inflammation and cancer,” Current Medicinal Chemistry, vol. 18, no. 15, pp. 2263–2271, 2011. View at Google Scholar
  87. M. Ladetto, S. Vallet, A. Trojan et al., “Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome,” Blood, vol. 105, no. 12, pp. 4784–4791, 2005. View at Publisher · View at Google Scholar · View at Scopus
  88. P. Mukherjee, G. D. Basu, T. L. Tinder et al., “Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition,” Journal of Immunology, vol. 182, no. 1, pp. 216–224, 2009. View at Google Scholar · View at Scopus
  89. A. Barber, T. Zhang, C. J. Megli, J. Wu, K. R. Meehan, and C. L. Sentman, “Chimeric NKG2D receptor-expressing T cells as an immunotherapy for multiple myeloma,” Experimental Hematology, vol. 36, no. 10, pp. 1318–1328, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. A. Barber, K. R. Meehan, and C. L. Sentman, “Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells,” Gene Therapy, vol. 18, no. 5, pp. 509–516, 2011. View at Publisher · View at Google Scholar · View at Scopus
  91. S. Peinert, H. M. Prince, P. M. Guru et al., “Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis y antigen,” Gene Therapy, vol. 17, no. 5, pp. 678–686, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. A. Liso, K. E. Stockerl-Goldstein, S. Auffermann-Gretzinger et al., “Idiotype vaccination using dendritic cells after autologous peripheral blood progenitor cell transplantation for multiple myeloma,” Biology of Blood and Marrow Transplantation, vol. 6, no. 6, pp. 621–627, 2000. View at Google Scholar · View at Scopus
  93. M. Q. Lacy, S. Mandrekar, A. Dispenzieri et al., “Idiotype-pulsed antigen presenting cells following autologous transplantation for multiple myeloma may be associated with prolonged survival,” American Journal of Hematology, vol. 84, no. 12, pp. 799–802, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. M. Massaia, P. Borrione, S. Battaglio et al., “Idiotype vaccination in human myeloma: generation of tumor-specific immune responses after high-dose chemotherapy,” Blood, vol. 94, no. 2, pp. 673–683, 1999. View at Google Scholar · View at Scopus
  95. V. L. Reichardt, C. Milazzo, W. Brugger, H. Einsele, L. Kanz, and P. Brossart, “Idiotype vaccination of multiple myeloma patients using monocyte-derived dendritic cells,” Haematologica, vol. 88, no. 10, pp. 1139–1149, 2003. View at Google Scholar · View at Scopus
  96. L. Hansson, A. O. Abdalla, A. Moshfegh et al., “Long-term idiotype vaccination combined with interleukin-12 (IL-12), or IL-12 and granulocyte macrophage colony-stimulating factor, in early-stage multiple myeloma patients,” Clinical Cancer Research, vol. 13, no. 5, pp. 1503–1510, 2007. View at Publisher · View at Google Scholar · View at Scopus
  97. F. S. Hodi, M. C. Mihm, R. J. Soiffer et al., “Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 8, pp. 4712–4717, 2003. View at Publisher · View at Google Scholar · View at Scopus
  98. F. S. Hodi, S. J. O'Day, D. F. McDermott et al., “Improved survival with ipilimumab in patients with metastatic melanoma,” New England Journal of Medicine, vol. 363, no. 8, pp. 711–723, 2010. View at Publisher · View at Google Scholar · View at Scopus
  99. P. Sharma, K. Wagner, J. D. Wolchok, and J. P. Allison, “Novel cancer immunotherapy agents with survival benefit: recent successes and next steps,” Nature Reviews Cancer, vol. 11, no. 11, pp. 805–812, 2011. View at Publisher · View at Google Scholar
  100. M. Arpinati, G. Chirumbolo, B. Nicolini, C. Agostinelli, and D. Rondelli, “Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade),” Bone Marrow Transplantation, vol. 43, no. 3, pp. 253–259, 2009. View at Publisher · View at Google Scholar · View at Scopus
  101. C. Straube, R. Wehner, M. Wendisch et al., “Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells,” Leukemia, vol. 21, no. 7, pp. 1464–1471, 2007. View at Publisher · View at Google Scholar · View at Scopus