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Scientifica
Volume 2013 (2013), Article ID 857519, 19 pages
http://dx.doi.org/10.1155/2013/857519
Review Article

Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 Blockade Therapy: The Underlying Mechanisms and Clinical Management

Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue, Room 555, Pittsburgh, PA 15232, USA

Received 6 December 2012; Accepted 10 January 2013

Academic Editors: D. Jun and M. H. Manjili

Copyright © 2013 Ahmad Tarhini. 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. J. G. van den Boorn, D. Konijnenberg, E. P. Tjin et al., “Effective melanoma immunotherapy in mice by the skin-depigmenting agent monobenzone and the adjuvants imiquimod and CpG,” PloS ONE, vol. 5, no. 5, Article ID e10626, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. M. Sznol, “Betting on immunotherapy for melanoma,” Current Oncology Reports, vol. 11, no. 5, pp. 397–404, 2009. View at Publisher · View at Google Scholar
  3. I. Komenaka, H. Hoerig, and H. L. Kaufman, “Immunotherapy for melanoma,” Clinics in Dermatology, vol. 22, no. 3, pp. 251–265, 2004. View at Publisher · View at Google Scholar · View at Scopus
  4. H. Gogas, J. Ioannovich, U. Dafni et al., “Prognostic significance of autoimmunity during treatment of melanoma with interferon,” The New England Journal of Medicine, vol. 354, no. 7, pp. 709–718, 2006. View at Publisher · View at Google Scholar · View at Scopus
  5. C. G. Clemente, M. C. Mihm Jr., R. Bufalino, S. Zurrida, P. Collini, and N. Cascinelli, “Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma,” Cancer, vol. 77, no. 7, pp. 1303–1310, 1996. View at Publisher · View at Google Scholar
  6. R. C. Taylor, A. Patel, K. S. Panageas, K. J. Busam, and M. S. Brady, “Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma,” Journal of Clinical Oncology, vol. 25, no. 7, pp. 869–875, 2007. View at Publisher · View at Google Scholar · View at Scopus
  7. A. Håkansson, B. Gustafsson, L. Krysander, and L. Håkansson, “Tumor-infiltrating lymphocytes in metastatic malignant melanoma and response to interferon alpha treatment,” The British Journal of Cancer, vol. 74, no. 5, pp. 670–676, 1996. View at Publisher · View at Google Scholar
  8. M. C. Mihm Jr., C. G. Clemente, and N. Cascinelli, “Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response,” Laboratory Investigation, vol. 74, no. 1, pp. 43–47, 1996. View at Scopus
  9. S. J. Moschos, H. D. Edington, S. R. Land et al., “Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses,” Journal of Clinical Oncology, vol. 24, no. 19, pp. 3164–3171, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. I. Mellman, G. Coukos, and G. Dranoff, “Cancer immunotherapy comes of age,” Nature, vol. 480, no. 7378, pp. 480–489, 2011. View at Publisher · View at Google Scholar
  11. J. S. Weber, K. C. Kähler, and A. Hauschild, “Management of immune-related adverse events and kinetics of response with ipilimumab,” Journal of Clinical Oncology, vol. 30, no. 21, pp. 2691–2697, 2012. View at Publisher · View at Google Scholar
  12. G. Q. Phan, J. C. Yang, R. M. Sherry, et al., “Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 14, pp. 8372–8377, 2003. View at Publisher · View at Google Scholar
  13. A. V. Maker, G. Q. Phan, P. Attia et al., “Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study,” Annals of Surgical Oncology, vol. 12, no. 12, pp. 1005–1016, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. K. J. Carpenter, R. D. Murtagh, H. Lilienfeld, J. Weber, and F. R. Murtagh, “Ipilimumab-induced hypophysitis: MR imaging findings,” The American Journal of Neuroradiology, vol. 30, no. 9, pp. 1751–1753, 2009. View at Publisher · View at Google Scholar · View at Scopus
  15. P. Attia, G. Q. Phan, A. V. Maker, et al., “Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4,” Journal of Clinical Oncology, vol. 23, no. 25, pp. 6043–6053, 2005. View at Publisher · View at Google Scholar
  16. F. S. Hodi, S. J. O’Day, D. F. McDermott, et al., “Improved survival with ipilimumab in patients with metastatic melanoma,” The New England Journal of Medicine, vol. 363, no. 8, pp. 711–723, 2010. View at Publisher · View at Google Scholar
  17. C. Robert, L. Thomas, I. Bondarenko, et al., “Ipilimumab plus dacarbazine for previously untreated metastatic melanoma,” The New England Journal of Medicine, vol. 364, no. 26, pp. 2517–2526, 2011. View at Publisher · View at Google Scholar
  18. J. Wolchok, B. Neyns, G. Linette, et al., “Ipilimumab monotherapy in patients with previously treated, advanced melanoma: a randomized, double-blind, multicenter, phase 2, dose-ranging study,” The Lancet Oncology, vol. 11, no. 2, pp. 155–164, 2010. View at Publisher · View at Google Scholar
  19. J. Weber, J. A. Thompson, O. Hamid et al., “A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma,” Clinical Cancer Research, vol. 15, no. 17, pp. 5591–5598, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. S. J. O’Day, M. Maio, V. Chiarion-Sileni, et al., “Efficacy and safety of ipilimumab monotherapy in patients with pretreated, advanced melanoma: a multicenter single-arm phase II study,” Annals of Oncology, vol. 21, no. 8, pp. 1712–1717, 2010. View at Publisher · View at Google Scholar
  21. E. M. Hersh, S. J. O'Day, J. Powderly et al., “A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma,” Investigational New Drugs, vol. 29, no. 3, pp. 489–498, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. D. M. Pardoll, “The blockade of immune checkpoints in cancer immunotherapy,” Nature Reviews Cancer, vol. 12, no. 4, pp. 252–264, 2012. View at Publisher · View at Google Scholar
  23. K. S. Peggs and S. A. Quezada, “Ipilimumab: attenuation of an inhibitory immune checkpoint improves survival in metastatic melanoma,” Expert Review of Anticancer Therapy, vol. 10, no. 11, pp. 1697–1701, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. R. Ibrahim, D. Berman, V. de Pril V, et al., “Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma,” Journal of Clinical Oncology, vol. 29, abstract no. 8583, 2011.
  25. R. Dummer, M. Maio, O. Hamid, et al., “Time to onset and resolution of immune-related adverse events associated with ipilimumab therapy in patients with advanced melanoma,” in Proceedings of the 14th Perspectives in Melanoma, abstract P-0004, Amsterdam, The Netherlands, September 2010.
  26. “YERVOY (ipilimumab): serious and fatal immune-mediated adverse reactions,” Ipilimumab US prescribing information: risk evaluation and mitigation strategy (REMS), Bristol-Myers Squibb, 2012, http://www.yervoy.com/hcp/rems.aspx.
  27. A. A. Tarhini and J. M. Kirkwood, “CTLA-4-blocking immunotherapy with ipilimumab for advanced melanoma,” Oncology, vol. 24, no. 14, pp. 1302–1304, 2010. View at Scopus
  28. E. L. Korn, P. Y. Liu, S. J. Lee et al., “Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials,” Journal of Clinical Oncology, vol. 26, no. 4, pp. 527–534, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. C. M. Balch, J. E. Gershenwald, S. J. Soong, et al., “Final version of 2009 AJCC melanoma staging and classification,” Journal of Clinical Oncology, vol. 27, no. 36, pp. 6199–6206, 2009. View at Publisher · View at Google Scholar
  30. J. M. Kirkwood, A. A. Tarhini, M. C. Panelli et al., “Next generation of immunotherapy for melanoma,” Journal of Clinical Oncology, vol. 26, no. 20, pp. 3445–3455, 2008. View at Publisher · View at Google Scholar
  31. S. S. Agarwala, “Current systemic therapy for metastatic melanoma,” Expert Review of Anticancer Therapy, vol. 9, no. 5, pp. 587–595, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. G. K. Antony and A. Z. Dudek, “Interleukin 2 in cancer therapy,” Current Medicinal Chemistry, vol. 17, no. 29, pp. 3297–3302, 2010.
  33. J. M. Kirkwood, L. H. Butterfield, A. A. Tarhini, H. Zarour, P. Kalinski, and S. Ferrone, “Immunotherapy of cancer in 2012,” CA: A Cancer Journal for Clinicians, vol. 62, no. 5, pp. 309–335, 2012. View at Publisher · View at Google Scholar
  34. J. R. Thumar and H. M. Kluger, “Ipilimumab: a promising immunotherapy for melanoma,” Oncology, vol. 24, no. 14, pp. 1280–1288, 2010. View at Scopus
  35. A. V. Maker, J. C. Yang, R. M. Sherry, et al., “Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma,” Journal of Immunotherapy, vol. 29, no. 4, pp. 455–463, 2006. View at Publisher · View at Google Scholar
  36. J. S. Weber, S. O’Day, W. Urba et al., “Phase I/II study of ipilimumab for patients with metastatic melanoma,” Journal of Clinical Oncology, vol. 26, no. 36, pp. 5950–5956, 2008. View at Publisher · View at Google Scholar
  37. J. Weber, “Ipilimumab: controversies in its development, utility, and autoimmune adverse events,” Cancer Immunology, Immunotherapy, vol. 58, no. 5, pp. 823–830, 2009. View at Publisher · View at Google Scholar
  38. L. Rivoltini, M. Carrabba, V. Huber et al., “Immunity to cancer: attack and escape in T lymphocyte-tumor cell interaction,” Immunological Reviews, vol. 188, pp. 97–113, 2002. View at Publisher · View at Google Scholar · View at Scopus
  39. I. Melero, S. Hervas-Stubbs, M. Glennie, D. M. Pardoll, and L. Chen, “Immunostimulatory monoclonal antibodies for cancer therapy,” Nature Reviews Cancer, vol. 7, no. 2, pp. 95–106, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. A. Hoos, R. Ibrahim, A. Korman et al., “Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy,” Seminars in Oncology, vol. 37, no. 5, pp. 533–546, 2010. View at Publisher · View at Google Scholar · View at Scopus
  41. J. Weber, “Immune checkpoint proteins: a new therapeutic paradigm for cancer—preclinical background: CTLA-4 and PD-1 blockade,” Seminars in Oncology, vol. 37, no. 5, pp. 430–439, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. P. Boasberg, O. Hamid, and S. O'Day, “Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade,” Seminars in Oncology, vol. 37, no. 5, pp. 440–449, 2010. View at Publisher · View at Google Scholar · View at Scopus
  43. D. Nagorsen, C. Scheibenbogen, F. M. Marincola, A. Letsch, and U. Keilholz, “Natural T cell immunity against cancer,” Clinical Cancer Research, vol. 9, no. 12, pp. 4296–4303, 2003. View at Scopus
  44. G. P. Dunn, A. T. Bruce, H. Ikeda, L. J. Old, and R. D. Schreiber, “Cancer immunoediting: from immunosurveillance to tumor escape,” Nature Immunology, vol. 3, no. 11, pp. 991–998, 2002. View at Publisher · View at Google Scholar · View at Scopus
  45. V. Shankaran, H. Ikeda, A. T. Bruce et al., “IFNγ, and lymphocytes prevent primary tumour development and shape tumour immunogenicity,” Nature, vol. 410, no. 6832, pp. 1107–1111, 2001. View at Publisher · View at Google Scholar · View at Scopus
  46. M. DuPage, C. Mazumdar, L. M. Schmidt, A. F. Cheung, and T. Jacks, “Expression of tumour-specific antigens underlies cancer immunoediting,” Nature, vol. 482, no. 7385, pp. 405–409, 2012. View at Publisher · View at Google Scholar
  47. F. Pandolfi, R. Cianci, S. Lolli et al., “Strategies to overcome obstacles to successful immunotherapy of melanoma,” International Journal of Immunopathology and Pharmacology, vol. 21, no. 3, pp. 493–500, 2008. View at Scopus
  48. J. T. Kurnick, T. Ramirez-Montagut, L. A. Boyle et al., “A novel autocrine pathway of tumor escape from immune recognition: melanoma cell lines produce a soluble protein that diminishes expression of the gene encoding the melanocyte lineage Melan-A/MART-1 antigen through down-modulation of its promoter,” Journal of Immunology, vol. 167, no. 3, pp. 1204–1211, 2001. View at Scopus
  49. D. I. Gabrilovich and S. Nagaraj, “Myeloid-derived suppressor cells as regulators of the immune system,” Nature Reviews Cancer, vol. 9, no. 3, pp. 162–174, 2009. View at Publisher · View at Google Scholar
  50. F. Pandolfi, R. Cianci, D. Pagliari et al., “The immune response to tumors as a tool toward immunotherapy,” Clinical and Developmental Immunology, vol. 2011, Article ID 894704, 12 pages, 2011. View at Publisher · View at Google Scholar
  51. D. T. Alexandrescu, T. E. Ichim, N. H. Riordan et al., “Immunotherapy for melanoma: current status and perspectives,” Journal of Immunotherapy, vol. 33, no. 6, pp. 570–579, 2010. View at Publisher · View at Google Scholar
  52. W. Wang, R. Lau, D. Yu, W. Zhu, A. Korman, and J. Weber, “PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+CD25Hi regulatory T cells,” International Immunology, vol. 21, no. 9, pp. 1065–1077, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. J. J. Engelhardt, T. J. Sullivan, and J. P. Allison, “CTLA-4 overexpression inhibits T cell responses through a CD28-B7-dependent mechanism,” Journal of Immunology, vol. 177, no. 2, pp. 1052–1061, 2006.
  54. T. Keler, E. Halk, L. Vitale et al., “Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques,” Journal of Immunology, vol. 171, no. 11, pp. 6251–6259, 2003. View at Scopus
  55. C. Robert and F. Ghiringhelli, “What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma?” Oncologist, vol. 14, no. 8, pp. 848–861, 2009. View at Publisher · View at Google Scholar · View at Scopus
  56. J. S. Weber, O. Hamid, S. D. Chasalow et al., “Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma,” Journal of Immunotherapy, vol. 35, no. 1, pp. 89–97, 2012. View at Publisher · View at Google Scholar
  57. J. R. Brahmer, S. S. Tykodi, L. Q. Chow, et al., “Safety and activity of anti-PD-L1 antibody in patients with advanced cancer,” The New England Journal of Medicine, vol. 366, no. 26, pp. 2455–2655, 2012. View at Publisher · View at Google Scholar
  58. D. Schadendorf, S. M. Algarra, L. Bastholt et al., “Immunotherapy of distant metastatic disease,” Annals of Oncology, vol. 20, supplement 6, pp. vi41–vi50, 2009. View at Publisher · View at Google Scholar
  59. B. Li, J. Lin, M. VanRoey, M. Jure-Kunkel, and K. Jooss, “Established B16 tumors are rejected following treatment with GM-CSF-secreting tumor cell immunotherapy in combination with anti-4-1BB mAb,” Clinical Immunology, vol. 125, no. 1, pp. 76–87, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. B. K. Choi, Y. H. Kim, W. J. Kang et al., “Mechanisms involved in synergistic anticancer immunity of anti-4-1BB and anti-CD4 therapy,” Cancer Research, vol. 67, no. 18, pp. 8891–8899, 2007. View at Publisher · View at Google Scholar
  61. M. Sznol, F. S. Hodi, K. Margolin, et al., “Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA). 2008 ASCO annual proceedings part I,” Journal of Clinical Oncology, vol. 26, abstract no. 3007, 2008.
  62. J. D. Wolchok, J. S. Weber, O. Hamid et al., “Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials,” Cancer Immunity, vol. 10, article 9, 2010. View at Scopus
  63. A. Farolfi, L. Ridolfi, M. Guidoboni et al., “Ipilimumab in advanced melanoma: reports of long-lasting responses,” Melanoma Research, vol. 22, no. 3, pp. 263–270, 2012. View at Publisher · View at Google Scholar
  64. P. A. Prieto, J. C. Yang, R. M. Sherry et al., “CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma,” Clinical Cancer Research, vol. 18, no. 7, pp. 2039–2047, 2012. View at Publisher · View at Google Scholar
  65. K. Heller, A. C. Pavlick, F. S. Hodi, et al., “Safety and survival analysis of ipilimumab therapy in patients with stable asymptomatic brain metastases,” Journal of Clinical Oncology, vol. 29, abstract no. 8581, 2011.
  66. K. Margolin, M. S. Ernstoff, O. Hamid, et al., “Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial,” The Lancet Oncology, vol. 13, no. 5, pp. 459–465, 2012. View at Publisher · View at Google Scholar
  67. J. D. Wolchok, A. Hoos, S. O’Day, et al., “Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria,” Clinical Cancer Research, vol. 15, no. 23, pp. 7412–7420, 2009. View at Publisher · View at Google Scholar
  68. A. Hoos, A. M. Eggermont, S. Janetzki, et al., “Improved endpoints for cancer immunotherapy trials,” Journal of the National Cancer Institute, vol. 102, no. 18, pp. 1388–1397, 2010. View at Publisher · View at Google Scholar
  69. A. M. Di Giacomo, M. Biagioli, and M. Maio, “The emerging toxicity profiles of antiCTLA-4 antibodies across clinical indications,” Seminars in Oncology, vol. 37, no. 5, pp. 499–507, 2010. View at Publisher · View at Google Scholar · View at Scopus
  70. K. C. Kaehler, S. Piel, E. Livingstone, B. Schilling, A. Hauschild, and D. Schadendorf, “Update on immunologic therapy with antiCTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management,” Seminars in Oncology, vol. 37, no. 5, pp. 485–498, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. S. Read, R. Greenwald, A. Izcue et al., “Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo,” Journal of Immunology, vol. 177, no. 7, pp. 4376–4383, 2006.
  72. A. J. Korman, K. S. Peggs, and J. P. Allison, “Checkpoint blockade in cancer immunotherapy,” Advances in Immunology, vol. 90, pp. 297–339, 2006. View at Publisher · View at Google Scholar · View at Scopus
  73. W. Féaux de Lacroix, U. Runne, H. Hauk, K. Doepfmer, W. Groth, and D. Wacker, “Acute liver dystrophy with thrombosis of hepatic veins: a fatal complication of dacarbazine treatment,” Cancer Treatment Reports, vol. 67, no. 9, pp. 779–784, 1983. View at Scopus
  74. M. Horiguchi, J. Kim, N. Matsunaga et al., “Glucocorticoid-dependent expression of O6-methylguanine-DNA methyltransferase gene modulates dacarbazine-induced hepatotoxicity in mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 3, pp. 782–787, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. “YERVOY (ipilimumab) Injection for intravenous infusion,” Ipilimumab US prescribing information 2011, Bristol-Myers Squibb, 2011, http://packageinserts.bms.com/pi/pi_yervoy.pdf.
  76. S. P. Patel and S. E. Woodman, “Profile of ipilimumab and its role in the treatment of metastatic melanoma,” Drug Design, Development and Therapy, vol. 5, pp. 489–495, 2011. View at Publisher · View at Google Scholar
  77. C. Lebbé, S. J. O’Day, V. C. Sileni, et al., “Analysis of the onset and resolution of immune-related adverse events during treatment with ipilimumab in patients with metastatic melanoma,” in Proceedings of the 12th Perspectives in Melanoma, abstract O-015, New York, NY, USA, October2008.
  78. M. E. Lacouture and B. L. Melosky, “Cutaneous reactions to anticancer agents targeting the epidermal growth factor receptor: a dermatology-oncology perspective,” Skin Therapy Letter, vol. 12, no. 6, pp. 1–5, 2007. View at Scopus
  79. M. Luu, S. L. Boone, J. Patel et al., “Higher severity grade of erlotinib-induced rash is associated with lower skin phototype,” Clinical and Experimental Dermatology, vol. 36, no. 7, pp. 733–738, 2011. View at Publisher · View at Google Scholar
  80. S. H. Jaber, E. W. Cowen, L. R. Haworth et al., “Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent,” Archives of Dermatology, vol. 142, no. 2, pp. 166–172, 2006. View at Publisher · View at Google Scholar · View at Scopus
  81. A. C. Pavlick, P. A. Ott, K. Kannan, et al., “Hair depigmentation as an indicator of a durable response to CTLA-4 therapy,” Journal of Clinical Oncology, vol. 28, article 15s, abstract no. 8571, 2010.
  82. D. A. Oble, M. Mino-Kenudson, J. Goldsmith et al., “Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis,” The American Journal of Surgical Pathology, vol. 32, no. 8, pp. 1130–1137, 2008. View at Publisher · View at Google Scholar
  83. D. Berman, S. M. Parker, J. Siegel et al., “Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma,” Cancer Immunity, vol. 10, article 11, 2010. View at Scopus
  84. K. E. Beck, J. A. Blansfield, K. Q. Tran et al., “Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4,” Journal of Clinical Oncology, vol. 24, no. 15, pp. 2283–2289, 2006. View at Publisher · View at Google Scholar · View at Scopus
  85. D. R. Minor, K. Chin, and M. Kashani-Sabet, “Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis,” Cancer Biotherapy and Radiopharmaceuticals, vol. 24, no. 3, pp. 321–325, 2009. View at Publisher · View at Google Scholar · View at Scopus
  86. J. D. Lord, R. C. Hackman, A. Moklebust et al., “Refractory colitis following anti-CTLA4 antibody therapy: analysis of mucosal FOXP3+ T cells,” Digestive Diseases and Sciences, vol. 55, no. 5, pp. 1396–1405, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. K. S. Peggs, S. A. Quezada, A. J. Korman, and J. P. Allison, “Principles and use of anti-CTLA4 antibody in human cancer immunotherapy,” Current Opinion in Immunology, vol. 18, no. 2, pp. 206–213, 2006. View at Publisher · View at Google Scholar · View at Scopus
  88. G. Q. Phan, J. S. Weber, and V. K. Sondak, “CTLA-4 blockade with monoclonal antibodies in patients with metastatic cancer: surgical issues,” Annals of Surgical Oncology, vol. 15, no. 11, pp. 3014–3021, 2008. View at Publisher · View at Google Scholar · View at Scopus
  89. H. J. Freeman, “Colitis associated with biological agents,” World Journal of Gastroenterology, vol. 18, no. 16, pp. 1871–1874, 2012.
  90. F. O. Smith, S. L. Goff, J. A. Klapper et al., “Risk of bowel perforation in patients receiving interleukin-2 after therapy with anti-CTLA 4 monoclonal antibody,” Journal of Immunotherapy, vol. 30, no. 1, article 130, 2007. View at Publisher · View at Google Scholar · View at Scopus
  91. F. Torino, A. Barnabei, L. de Vecchis, R. Salvatori, and S. M. Corsello, “Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease,” The Oncologist, vol. 17, no. 4, pp. 525–535, 2012. View at Publisher · View at Google Scholar
  92. A. Juszczak, A. Gupta, N. Karavitaki, M. R. Middleton, and A. B. Grossman, “Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review,” European Journal of Endocrinology, vol. 167, no. 1, pp. 1–5, 2012. View at Publisher · View at Google Scholar
  93. J. R. Thurmar and H. M. Kluger, “Ipilimumab: a promising immunotherapy for melanoma,” Oncology, vol. 24, no. 14, pp. 1280–1288, 2010.
  94. L. Min, A. Vaidya, and C. Becker, “Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy,” European Journal of Endocrinology, vol. 164, no. 2, pp. 303–307, 2011. View at Publisher · View at Google Scholar · View at Scopus
  95. G. Borodic, D. M. Hinkle, and Y. Cia, “Drug-induced graves disease from CTLA-4 receptor suppression,” Ophthalmic Plastic and Reconstructive Surgery, vol. 27, no. 4, pp. e87–e88, 2011. View at Publisher · View at Google Scholar · View at Scopus
  96. G. Hunter, C. Voll, and C. A. Robinson, “Autoimmune inflammatory myopathy after treatment with ipilimumab,” Canadian Journal of Neurological Sciences, vol. 36, no. 4, pp. 518–520, 2009. View at Scopus
  97. J. C. Yang, M. Hughes, U. Kammula et al., “Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis,” Journal of Immunotherapy, vol. 30, no. 8, pp. 825–830, 2007. View at Publisher · View at Google Scholar · View at Scopus
  98. F. Bompaire, C. Mateus, H. Taillia et al., “Severe meningo-radiculo-nevritis associated with ipilimumab,” Investigational New Drugs, vol. 30, no. 6, pp. 2407–2410, 2012. View at Publisher · View at Google Scholar
  99. S. Wilgenhof and B. Neyns, “Anti-CTLA-4 antibody-induced Guillain-Barré syndrome in a melanoma patient,” Annals of Oncology, vol. 22, no. 4, pp. 991–993, 2011. View at Publisher · View at Google Scholar · View at Scopus
  100. S. Bhatia, B. R. Huber, M. P. Upton, and J. A. Thompson, “Inflammatory enteric neuropathy with severe constipation after ipilimumab treatment for melanoma: a case report,” Journal of Immunotherapy, vol. 32, no. 2, pp. 203–205, 2009. View at Publisher · View at Google Scholar · View at Scopus
  101. M. Maur, C. Tomasello, A. Frassoldati, M. V. Dieci, E. Barbieri, and P. Conte, “Posterior reversible encephalopathy syndrome during ipilimumab therapy for malignant melanoma,” Journal of Clinical Oncology, vol. 30, no. 6, pp. e76–e78, 2012. View at Publisher · View at Google Scholar
  102. A. M. Di Giacomo, R. Danielli, M. Guidoboni et al., “Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases,” Cancer Immunology, Immunotherapy, vol. 58, no. 8, pp. 1297–1306, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. I. O. Gordon, T. Wade, K. Chin, J. Dickstein, and T. F. Gajewski, “Immune-mediated red cell aplasia after anti-CTLA-4 immunotherapy for metastatic melanoma,” Cancer Immunology, Immunotherapy, vol. 58, no. 8, pp. 1351–1353, 2009. View at Publisher · View at Google Scholar · View at Scopus
  104. A. M. Di Giacomo, R. Danielli, L. Calabrò et al., “Ipilimumab experience in heavily pretreated patients with melanoma in an expanded access program at the University Hospital of Siena (Italy),” Cancer Immunology, Immunotherapy, vol. 60, no. 4, pp. 467–477, 2011. View at Publisher · View at Google Scholar · View at Scopus
  105. M. Akhtari, E. K. Waller, D. L. Jaye et al., “Neutropenia in a patient treated with ipilimumab (anti-CTLA-4 Antibody),” Journal of Immunotherapy, vol. 32, no. 3, pp. 322–324, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. S. Wilgenhof, V. Morlion, A. C. Seghers et al., “Sarcoidosis in a patient with metastatic melanoma sequentially treated with anti-CTLA-4 monoclonal antibody and selective BRAF inhibitor,” Anticancer Research, vol. 32, no. 4, pp. 1355–1359.
  107. W. V. Vogel, A. Guislain, P. Kvistborg, T. N. Schumacher, J. B. Haanen, and C. U. Blank, “Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission,” Journal of Clinical Oncology, vol. 30, no. 2, pp. e7–e10, 2012. View at Publisher · View at Google Scholar
  108. A. Eckert, A. Schoeffler, S. Dalle, A. Phan, L. Kiakouama, and L. Thomas, “Anti-CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient,” Dermatology, vol. 218, no. 1, pp. 69–70, 2009. View at Publisher · View at Google Scholar
  109. F. Fadel, K. El Karoui, and B. Knebelmann, “Anti-CTLA4 antibody-induced lupus nephritis,” The New England Journal of Medicine, vol. 361, no. 2, pp. 211–212, 2009. View at Scopus
  110. J. Delyon, C. Mateus, and T. Lambert, “Hemophilia A induced by ipilimumab,” The New England Journal of Medicine, vol. 365, no. 18, pp. 1747–1748, 2011. View at Publisher · View at Google Scholar
  111. J. Lozier, “More on hemophilia A induced by ipilimumab,” The New England Journal of Medicine, vol. 366, no. 3, pp. 280–281, 2012.
  112. J. Lutzky, J. Wolchok, O. Hamid, et al., “Association between immune-related adverse events (irAEs) and disease control or overall survival in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials,” Journal of Clinical Oncology, vol. 27, article 469s, abstract no. 9034, 2009.
  113. A. A. Tarhini, J. Cherian, S. J. Moschos et al., “Safety and efficacy of combination immunotherapy with interferon alfa-2b and tremelimumab in patients with stage IV melanoma,” Journal of Clinical Oncology, vol. 30, no. 3, pp. 322–328, 2012. View at Publisher · View at Google Scholar
  114. Y. Bronstein, C. S. Ng, P. Hwu, and W. J. Hwu, “Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy,” The American Journal of Roentgenology, vol. 197, no. 6, pp. W992–W1000, 2011. View at Publisher · View at Google Scholar
  115. R. R. Ji, S. D. Chasalow, L. Wang et al., “An immune-active tumor microenvironment favors clinical response to ipilimumab,” Cancer Immunology, Immunotherapy, vol. 61, no. 7, pp. 1019–1031, 2012. View at Publisher · View at Google Scholar
  116. S. J. O'Day, O. Hamid, and W. J. Urba, “Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies,” Cancer, vol. 110, no. 12, pp. 2614–2627, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. A. Amin, V. DePril, O. Hamid, et al., “Evaluation of the effect of systemic corticosteroids for the treatment of immune-related adverse events (irAEs) on the development or maintenance of ipilimumab clinical activity,” Journal of Clinical Oncology, vol. 27, article 15s, abstract no. 9037, 2009.
  118. K. Harmankaya, C. Erasim, C. Koelblinger et al., “Continuous systemic corticosteroids do not affect the ongoing regression of metastatic melanoma for more than two years following ipilimumab therapy,” Medical Oncology, vol. 28, no. 4, pp. 1140–1144, 2011. View at Publisher · View at Google Scholar
  119. J. J. Grob, O. Hamid, J. Wolchok, et al., “Antitumor responses to ipilimumab in advanced melanoma are not affected by systemic corticosteroids used to manage immune-related adverse events (irAEs),” in Proceedings of the Joint ECCO 15–34th ESMO Multidisciplinary Congress, abstract P-9312, Berlin, Germany, September 2009.
  120. S. G. Downey, J. A. Klapper, F. O. Smith, et al., “Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade,” Clinical Cancer Research, vol. 13, no. 22, part 1, pp. 6681–6688, 2007.
  121. C. Lemech and H. T. Arkenau, “Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities,” Clinical Medicine Insights, Oncology, vol. 6, pp. 53–66, 2012. View at Publisher · View at Google Scholar
  122. A. Tarhini, E. Lo, and D. R. Minor, “Releasing the brake on the immune system: ipilimumab in melanoma and other tumors,” Cancer Biotherapy and Radiopharmaceuticals, vol. 25, no. 6, pp. 601–613, 2010. View at Publisher · View at Google Scholar · View at Scopus
  123. C. Verschraegen, “. The monoclonal antibody to cytotoxic T lymphocyte antigen 4, ipilimumab, in the treatment of melanoma,” Cancer Management and Research, vol. 4, pp. 1–8, 2012. View at Publisher · View at Google Scholar
  124. K. M. Rubin, “Managing immune-related adverse events to ipilimumab: a nurse's guide,” Clinical Journal of Oncology Nursing, vol. 16, no. 2, pp. E69–E75, 2012. View at Publisher · View at Google Scholar
  125. S. O’Day, J. S. Weber, J. D. Wolchok, et al., “Effectiveness of treatment guidance on diarrhea and colitis across ipilimumab studies,” Journal of Clinical Oncology, vol. 29, abstract no. 8554, 2011.
  126. K. C. Kaehler, F. Egberts, P. Lorigan, and A. Hauschilda, “Anti-CTLA-4 therapy-related autoimmune hypophysitis in a melanoma patient,” Melanoma Research, vol. 19, no. 5, pp. 333–334, 2009. View at Publisher · View at Google Scholar · View at Scopus
  127. K. D. Chmiel, D. Suan, C. Liddle et al., “Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy,” Journal of Clinical Oncology, vol. 29, no. 9, pp. e237–e240, 2011. View at Publisher · View at Google Scholar
  128. “REMICADE (infliximab) Lyophilized concentrate for injection, for intravenous use,” Infliximab US prescribing information 2012, Janssen Biotech, Inc., 2012, http://www.remicade.com/remicade/assets/hcp_ppi.pdf.
  129. A. A. Tarhini and F. Iqbal, “CTLA-4 blockade: therapeutic potential in cancer treatments,” OncoTargets and Therapy, vol. 3, pp. 15–25, 2010. View at Scopus