Endocrine side effects induced by immune checkpoint inhibitors

Journal of Clinical Endocrinology and Metabolism

Volumn 98, Issue 4, 2013, Pages 1361-1375

  Corsello, Salvatore Maria ^a   Barnabei, Agnese ^b   Marchetti, Paolo ^c   De Vecchis, Liana ^d   Salvatori, Roberto ^e   Torino, Francesco ^d  

^a CATHOLIC UNIVERSITY   (Italy)

^b REGINA ELENA NATIONAL CANCER INSTITUTE   (Italy)

^c SAPIENZA UNIVERSITY OF ROME   (Italy)

^d UNIVERSITY OF ROME TOR VERGATA   (Italy)

^e JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BEVACIZUMAB; CANCER VACCINE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 ANTIBODY; DACARBAZINE; FOTEMUSTINE; GLUCOCORTICOID; GLYCOPROTEIN GP 100; IMMUNE CHECKPOINT INHIBITOR; IMMUNOMODULATING AGENT; IMMUNOSUPPRESSIVE AGENT; IPILIMUMAB; PEPTIDE VACCINE; PLACEBO; PROGRAMMED DEATH 1 INHIBITOR; PROGRAMMED DEATH 1 LIGAND INHIBITOR; PROGRAMMED DEATH 1 RECEPTOR; PROSTATE SPECIFIC ANTIGEN VACCINE; RECOMBINANT INTERLEUKIN 2; TICILIMUMAB; TUMOR ANTIGEN; UNCLASSIFIED DRUG;

ABDOMINAL PAIN; ADRENAL INSUFFICIENCY; ADVANCED CANCER; AMNESIA; ANOREXIA; ARTHRALGIA; ARTHRITIS; ASEPTIC MENINGITIS; ASTHENIA; ASTHMA; AUTOIMMUNE DISEASE; AUTOIMMUNE THYROIDITIS; AUTOINFLAMMATORY DISEASE; BEHAVIOR CHANGE; BONE MARROW TOXICITY; CANCER SURVIVAL; CASTRATION RESISTANT PROSTATE CANCER; CELL PROLIFERATION; CELLULITIS; CHILL; CLINICAL FEATURE; COLITIS; COLORECTAL CANCER; CONFUSION; CONSTIPATION; CUTANEOUS MELANOMA; DERMATITIS; DIARRHEA; DIPLOPIA; DOSE RESPONSE; DOWN REGULATION; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG ERUPTION; DRUG FATALITY; DRUG FEVER; DRUG INDUCED HEADACHE; EDEMA; ENCEPHALITIS; ENDOCRINE DISEASE; ENTEROCOLITIS; ENZYME BLOOD LEVEL; EUTHYROID SICK SYNDROME; FATIGUE; GASTROINTESTINAL HEMORRHAGE; GASTROINTESTINAL SYMPTOM; GIANT CELL ARTERITIS; HALLUCINATION; HOMEOSTASIS; HORMONE SUBSTITUTION; HUMAN; HYPERTHYROIDISM; HYPERTRANSAMINASEMIA; HYPOGONADOTROPIC HYPOGONADISM; HYPOKALEMIA; HYPOPHYSITIS; HYPOPITUITARISM; HYPOTHYROIDISM; IMMUNOLOGICAL TOLERANCE; INFUSION RELATED REACTION; INSOMNIA; INTESTINAL BLEEDING; INTESTINE PERFORATION; INTRACELLULAR SIGNALING; KIDNEY CARCINOMA; LIBIDO DISORDER; LIVER DISEASE; LUNG NON SMALL CELL CANCER; LYMPHOCYTIC AUTOIMMUNE HYPOPHYSITIS; MELANOMA; MORNING DOSAGE; MULTIPLE CYCLE TREATMENT; MULTIPLE ORGAN FAILURE; NAUSEA; NEUTROPENIA; OVERALL SURVIVAL; PAIN; PANCYTOPENIA; PNEUMONIA; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN FUNCTION; PROTEIN SYNTHESIS INHIBITION; PRURITUS; REVIEW; SIDE EFFECT; SKIN DISEASE; SKIN EXFOLIATION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TEMPERATURE SENSITIVITY; THROMBOCYTE COUNT; THYROID DISEASE; THYROID FUNCTION TEST; THYROIDITIS; THYROTROPIN BLOOD LEVEL; TOXIC HEPATITIS; TREATMENT OUTCOME; TRIACYLGLYCEROL LIPASE BLOOD LEVEL; UVEITIS; VASCULITIS; VERTIGO; VISUAL IMPAIRMENT; WEAKNESS;

ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; CELL CYCLE CHECKPOINTS; CTLA-4 ANTIGEN; DRUG TOXICITY; ENDOCRINE SYSTEM; ENDOCRINE SYSTEM DISEASES; HUMANS; IMMUNOTHERAPY; NEOPLASMS;

EID: 84876248304     PISSN: 0021972X     EISSN: 19457197     Source Type: Journal    
DOI: 10.1210/jc.2012-4075     Document Type: Review

References (108)

1. Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007;121:1-14.
2. Stewart TJ, Smyth MJ. Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer Metastasis Rev. 2011;30:125-140.
3. Dillman RO. Cancer immunotherapy. Cancer Biother Radiopharm. 2011;26:1-64.
4. Postow M, Callahan MK, Wolchok JD. Beyond cancer vaccines: a reason forfuture optimism with immunomodulatory therapy. Cancer J. 2011;17:372-378.
5. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734-1736.
6. Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer. 2011;11:805-812.
7. Tarhini A, Lo E, Minor DR. Releasing the brake on the immune system: ipilimumab in melanoma and other tumors. Cancer Biother Radiopharm. 2010;25:601-613.
8. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
9. Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin Oncol. 2010;37:499-507.
10. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005; 23:6043-6053.
11. Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30:825-830.
12. Fong L, Small EJ. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol. 2008;26:5275-5283.
13. Torino F, Barnabei A, De Vecchis L, Salvatori R, Corsello SM. Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist. 2012;17:525-535.
14. Caturegli P, Newschaffer C, Olivi A, Pomper MG, Burger PC, Rose NR. Autoimmune hypophysitis. Endocr Rev. 2005;26:599-614.
15. Ascierto PA, Simeone E, Sznol M, Fu YX, Melero I. Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies. Semin Oncol. 2010;37:508-516.
16. Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator. Immunity. 1997;7:445-450.
17. Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev. 2008;224:141-165.
18. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.
19. Ribas A, Hauschild A, Kefford R, et al. Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma. J Clin Oncol. 2008;26(suppl): 9011(Abstract).
20. Ledford H. Melanoma drug wins USapproval. Nature. 2011;471: 561.
21. Hanaizi Z, van Zwieten-Boot B, Calvo G, et al. The European Medicines Agency review of ipilimumab (Yervoy) for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Eur J Cancer. 2012;48:237-242.
22. O'Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer. 2007;110:2614-2627.
23. Lebbé C, O'Day S, Chiarion Sileni V, et al. Analysis of the onset and resolution of immune-related adverse events during treatment with ipilimumab in patients with metastatic melanoma. In: Proceedings from Perspectives in Melanoma XII; October 2-4, 2008; Scheveningen, the Hague, the Netherlands. Abstract O-015.
24. Rubin KM. Managing immune-related adverse events to ipilimumab: a nurse's guide. Clin J Oncol Nurs. 2012;16:E69-E75.
25. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-2697.
26. Yervoy (ipilimumab): serious and fatal immune-mediated adverse reactions. www.yervoy.com/hcp/rems.
27. Agarwala SS, Ribas A. Current experience with CTLA4-blocking monoclonal antibodies for the treatment of solid tumors. J Immunother. 2010;33:557-569.
28. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13: 6681-6688.
29. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28:593-598.
30. Maker AV, Yang JC, Sherry RM, et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 2006;29:455-463.
31. Madan RA, Mohebtash M, Arlen PM, et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: aphase 1dose-escalation trial. Lancet Oncol. 2012;13:501-518.
32. van den Eertwegh AJ, Versluis J, van den Berg HP, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:509-517.
33. Hodi FS, Friedlander PA, Atkins MB, et al. A phase I trial of ipilimumab plus bevacizumab in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2011;29:8511 (Abstract).
34. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, doubleblind, multicenter phase 2 trial. Ann Oncol. 2013;24:75-83.
35. Di Giacomo AM, Ascierto PA, Pilla L, et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol. 2012;13:879-886.
36. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results fromarandomized, double-blind, multicenter phaseIIstudy. J Clin Oncol. 2012;30:2046-2054.
37. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459-465.
38. Kaehler KC, Piel S, Livingstone E, Schilling B, Hauschild A, Schadendorf D. Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. Semin Oncol. 2010;37:485-498.
39. Dillard T, Yedinak CG, Alumkal J, Fleseriu M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary. 2010;13:29-38.
40. Juszczak A, Gupta A, Karavitaki N, Middleton MR, Grossman AB. Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review. Eur J Endocrinol. 2012;167:1-5.
41. Carpenter KJ, Murtagh RD, Lilienfeld H, Weber J, Murtagh FR. Ipilimumab-induced hypophysitis: MR imaging findings. AJNR Am J Neuroradiol. 2009;30:1751-1753.
42. Min L, Vaidya A, Becker C. Association of ipilimumab therapy for advanced melanoma with secondary adrenal insufficiency: a case series. Endocr Pract. 2012;18:351-355.
43. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA. 2003;100:8372-8377.
44. Maker AV, Phan GQ, Attia P, 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. Ann Surg Oncol. 2005;12:1005-1016.
45. Weber J. Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with ipilimumab MDX-010). Oncologist. 2008; 13(suppl 4):16-25.
46. Boasberg P, Hamid O, O'Day S. Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade. Semin Oncol. 2010;37:440-449.
47. Hinrichs CS, Palmer DC, Rosenberg SA, Restifo NP. Glucocorticoids do not inhibit antitumor activity of activated CD8 + T cells. J Immunother. 2005;28:517-524.
48. Min L, Vaidya A, Becker C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol. 2011;164:303-307.
49. Borodic G, Hinkle DM, Cia Y. Drug-induced Graves' disease from CTLA-4 receptor suppression. Ophthal Plast Reconstr Surg. 2011; 27:e87-e88.
50. Kirkwood JM, Lorigan P, Hersey P, et al. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res. 2010;16:1042-1048.
51. Di Giacomo AM, Danielli R, Calabrò L, et al. Ipilimumab experience in heavily pretreated patients with melanoma in an expanded access program at the University Hospital of Siena (Italy). Cancer Immunol Immunother. 2011;60:467-477.
52. Weber JS, O'Day S, Urba W, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26: 5950-5956.
53. Hersh EM, O'Day SJ, Powderly J, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs. 2011;29: 489-498.
54. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Ann Rev Immunol. 2008;26:677-704.
55. Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114:1537-1544.
56. Mumprecht S, Schurch C, Schwaller J, Solenthaler M, Ochsenbein AF. Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood. 2009;114:1528-1536.
57. Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009;114:1545-1552.
58. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.
59. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-2465.
60. Hamnvik OP, Larsen PR, Marqusee E. Thyroid dysfunction from antineoplastic agents. J Natl Cancer Inst. 2011;103:1572-1587.
61. Yeung SC, Chiu AC, Vassilopoulou-Sellin R, Gagel RF. The endocrine effects of nonhormonal antineoplastic therapy. Endocr Rev. 1998;19:144-172.
62. Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol. 2009;6:219-228.
63. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.
64. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24:2283-2289.
65. Klein O, Ebert LM, Nicholaou T, et al. Melan-A-specific cytotoxic T cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4. Clin Cancer Res. 2009;15: 2507-2513.
66. Caturegli P, Lupi I, Landek-Salgado M, Kimura H, Rose NR. Pituitary autoimmunity: 30 years later. Autoimm Rev. 2008;7:631-637.
67. Gutenberg A, Buslei R, Fahlbusch R, Buchfelder M, Brück W. Immunopathology of primary hypophysitis: implications for pathogenesis. Am J Surg Pathol. 2005;29:329-338.
68. Landek-Salgado MA, Tzou SC, Kimura H, Caturegli P. Induction of experimental autoimmune hypophysitis in SJL mice. J Vis Exp. 2010;17:46. doi:10.3791/2182.
69. Howlett TA, Levy MJ, Robertson IJ. How reliably can autoimmune hypophysitis be diagnosed without pituitary biopsy. Clin Endocrinol (Oxf). 2010;73:18-21.
70. Mirocha S, Elagin RB, Salamat S, Jaume JC. T regulatory cells distinguish two types of primary hypophysitis. Clin Exp Immunol. 2009;155:403-411.
71. Fasset DR, Couldwell WT. Metastases to the pituitary gland. Neurosurg Focus. 2004;16:E8.
72. Moshkin O, Rotondo F, Scheithauer BW, et al. Bronchial carcinoid tumors metastatic to the sella turcica and review of the literature. Pituitary. 2012;15:160-165.
73. Peppa M, Papaxoinis G, Xiros N, Raptis SA, Economopoulos T, Hadjidakis D. Panhypopituitarism due to metastases to the hypothalamus and the pituitary resulting from primary breast cancer: a case report and review of the literature. Clin Breast Cancer. 2009; 9:E4-E7.
74. Goglia U, Ferone D, Sidoti M, et al. Treatment of a pituitary metastasis from a neuroendocrine tumour: case report and literature review. Pituitary. 2008;11:93-102.
75. Alacaciolu A, Oztop I, Fidan F, et al. Diabetes insipidus caused by pituitary gland metastasis accompanied by iris metastasis of small cell lung cancer: case presentation and review of the literature. Tumori. 2008;94:765-768.
76. Basaria S, Westra WH, Brem H, Salvatori R. Metastatic renal cell carcinoma to the pituitary presenting with hyperprolactinemia. J Endocrinol Invest. 2004;27:471-474.
77. Hasham A, Tomer Y. Genetic and epigenetic mechanisms in thyroid autoimmunity. Immunol Res. 2012;54:204-213.
78. Vialettes B, Guillerand MA, Viens P, et al. Incidence rate and risk factors for thyroid dysfunction during recombinant interleukin-2 therapy in advanced malignancies. Acta Endocrinol (Copenh). 1993;129:31-38.
79. Vassilopoulou-Sellin R, Sella A, Dexeus FH, Theriault RL, Pololoff DA. Acute thyroid dysfunction (thyroiditis) after therapy with interleukin-2. Horm Metab Res. 1992;24:434-438.
80. Sauter NP, Atkins MB, Mier JW, Lechan RM. Transient thyrotoxicosis and persistent hypothyroidism due to acute autoimmune thyroiditis after interleukin-2 and interferon - α therapy for metastatic carcinoma: a case report. Am J Med. 1992;92:441-444.
81. Pichert G, Jost LM, Zobeli L, Odermatt B, Pedia G, Stahel RA. Thyroiditis after treatment with interleukin-2 and interferon a-2a. Br J Cancer. 1990;62:100-104.
82. Weijl NI, Van der Harst D, Brand A, et al. Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment. J Clin Oncol. 1993;11: 1376-1383.
83. Schwartzentruber DJ, White DE, Zweig MH, Weintraub BD, Rosenberg SA. Thyroid dysfunction associated with immunotherapy for patients with cancer. Cancer. 1991;68:2384-2390.
84. Kragel AH, Travis WD, Feinberg L, et al. Pathologic findings associated with interleukin-2-based immunotherapy for cancer: a postmortem study of 19 patients. Hum Pathol. 1990;21:493-502.
85. Sakane N, Yoshida T, Yoshioka K, Umekawa T, Kondo M, Shimatsu A. Reversible hypopituitarism after interferon-α therapy. Lancet. 1995;345:1305.
86. Concha LB, Carlson HE, Heimann A, Lake-Bakaar GV, Paal AF. Interferon-induced hypopituitarism. Am J Med. 2003;114:161-163.
87. Chan WB, Cockram CS. Panhypopituitarism in association with interferon-α treatment. Singapore Med J. 2004;45:93-94.
88. Tebben PJ, Atkinson JL, Scheithauer BW, Erickson D. Granulomatous adenohypophysitis after interferon and ribavirin therapy. Endocr Pract. 2007;13:169-175.
89. Ridruejo E, Christensen AF, Mando OG. Central hypothyroidism and hypophysitis during treatment of chronic hepatitis C with pegylated interferon a and ribavirin. Eur J Gastroenterol Hepatol. 2006;18:693-694.
90. Wolchok JD, Weber JS, Hamid O, et al. Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. Cancer Immun. 2010;10:9.
91. Camprubí C, Monk D. Does genomic imprinting play a role in autoimmunity? Adv Exp Med Biol. 2011;711:103-116.
92. Ganesh BB, Bhattacharya P, Gopisetty A, Prabhakar BS. Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity. J Interferon Cytokine Res. 2011;31:721-731.
93. Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA. 2003;100:4712-4717.
94. Johnston RL, Lutzky J, Chodhry A, Barkin JS. Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab. Dig Dis Sci. 2009;54:2538-2540.
95. http://evs.nci.nih.gov/ftp1/ctcae. Accessed December 2012.
96. Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828-833.
97. Weber JS, Targan S, Scotland R, et al. Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multi-peptide vaccine for resected stages IIIC and IV melanoma. J Clin Oncol. 2006;24(suppl): 2510(Abstract).
98. Fong L, Kavanagh B, Rini BI, et al. Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res. 2009; 69:609-615.
99. Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2007;13:1810-1815.
100. Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B cell non-Hodgkin lymphoma. Clin Cancer Res. 2009;15:6446-6453.
101. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.
102. O'Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712-1717.
103. Ku GY, Yuan J, Page DB, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after2doses correlates with survival. Cancer. 2010;116:1767-1775.
104. Hamid O, Hwu WJ, Richards JM, et al. Ipilimumab (Ipi) expanded access program (EAP) for patients (pts) with stage III/IV melanoma: 10 mg/kg cohort interim results. J Clin Oncol. 2012;30: 8508(Abstract).
105. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses ina phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005;23:8968-8977.
106. Camacho LH, Antonia S, Sosman J, et al. Phase I/II trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol. 2009;27:1075-1081.
107. Ralph C, Elkord E, Burt DJ, et al. Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res. 2010;16:1662-1672.
108. Chung KY, Gore I, Fong L, et al. PhaseII study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol. 2010;28:3485-3490.