Immunomodulation with the anti-CTLA-4 monoclonal antibody ipilimumab has been shown to extend overall survival (OS) in previously treated and treatment-naive patients with unresectable stage III or IV melanoma. Blockade of CTLA-4 signaling with ipilimumab prolongs T-cell activation and restores T-cell proliferation, thus amplifying T-cell-mediated immunity and the patient's capacity to mount an effective antitumor immune response. While this immunostimulation has unprecedented OS benefits in the melanoma setting, it can also result in immune-mediated effects on various organ systems, leading to immune-related adverse events (irAEs). Ipilimumab-associated irAEs are common and typically low grade and manageable, but can also be serious and life threatening. The skin and gastrointestinal tract are most frequently affected, while hepatic, endocrine, and neurologic events are less common. With proper management, most irAEs resolve within a relatively short time, with a predictable resolution pattern. Prompt and appropriate management of these irAEs is essential and treatment guidelines have been developed to assist oncologists and their teams. Implementation of these irAE management algorithms will help ensure that patients are able to benefit from ipilimumab therapy with adequate control of toxicities. 1. Introduction Melanoma is considered an “immunogenic” tumor—a theory that is supported by several observations and reported in the literature. The host immune system actively responds to melanoma, where advanced malignancy has rarely been reported to undergo spontaneous regression [1–4]. This may also be supported by the presence of lymphoid infiltrates at the site of primary melanoma associated with pathologic evidence of tumor regression. T-cell infiltration in primary melanoma was shown to be independently prognostic of improved survival [5]. Moreover, the absence of tumor infiltrating lymphocytes (TILs) at the primary melanoma site was associated with a higher probability of sentinel lymph node (SLN) melanoma metastasis compared with brisk TILs [6]. In patients treated with interferon-α2b (INFα2b), T-cell infiltration within nodal metastasis was associated with benefit from INFα2b therapy [7–9]. Clinically, this is also supported by the fact that for three decades, the only two therapeutic agents approved by the US Food and Drug Administration for the treatment of melanoma were immunotherapeutic (adjuvant IFNα and high-dose interleukin-2). Until recent regulatory approvals, patients with advanced melanoma have had few therapeutic options [27], and
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.
[2]
M. Sznol, “Betting on immunotherapy for melanoma,” Current Oncology Reports, vol. 11, no. 5, pp. 397–404, 2009.
[3]
I. Komenaka, H. Hoerig, and H. L. Kaufman, “Immunotherapy for melanoma,” Clinics in Dermatology, vol. 22, no. 3, pp. 251–265, 2004.
[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.
[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.
[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.
[7]
A. H？kansson, B. Gustafsson, L. Krysander, and L. H？kansson, “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.
[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.
[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.
[10]
I. Mellman, G. Coukos, and G. Dranoff, “Cancer immunotherapy comes of age,” Nature, vol. 480, no. 7378, pp. 480–489, 2011.
[11]
J. S. Weber, K. C. K？hler, 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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-na？ve patients with advanced melanoma,” Investigational New Drugs, vol. 29, no. 3, pp. 489–498, 2011.
[22]
D. M. Pardoll, “The blockade of immune checkpoints in cancer immunotherapy,” Nature Reviews Cancer, vol. 12, no. 4, pp. 252–264, 2012.
[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.
[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.
[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.
[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.
[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.
[31]
S. S. Agarwala, “Current systemic therapy for metastatic melanoma,” Expert Review of Anticancer Therapy, vol. 9, no. 5, pp. 587–595, 2009.
[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.
[34]
J. R. Thumar and H. M. Kluger, “Ipilimumab: a promising immunotherapy for melanoma,” Oncology, vol. 24, no. 14, pp. 1280–1288, 2010.
[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.
[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.
[37]
J. Weber, “Ipilimumab: controversies in its development, utility, and autoimmune adverse events,” Cancer Immunology, Immunotherapy, vol. 58, no. 5, pp. 823–830, 2009.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
