Abstract
A promising new class of anti-cancer drugs includes antibodies that mediate immune regulatory effects. It has become very clear over the last decade that different types of immune cells and different pathways serve to suppress anti-cancer immunity, particularly in the microenvironment of the tumor. The first examples of immune modulating antibodies are those directed against cytotoxic T lymphocyte antigen-4 (CTLA-4), a molecule present on activated T cells. Human antibodies that abrogate the function of CTLA-4 have been tested in the clinic and found to have clinical activity against melanoma. In this review, we discuss some of the controversies surrounding the potential clinical utility of one of those antibodies, ipilimumab, formerly MDX-010, from Medarex and Bristol Myers Squibb. The optimal dose and schedule of ipilimumab was derived in multiple clinical trials whose latest results are described below. Favorable survival in patients with stage IV melanoma were observed that appear to be associated with unique side effects of the drug called “immune-related adverse events”. The management of these side effects is described, and the unusual kinetics of anti-tumor response with ipilimumab as well as a newly proposed schema for assessing anti-tumor responses in patients receiving biologic compounds like ipilimumab, which may supercede RECIST or WHO criteria, are addressed.
Similar content being viewed by others
References
Chambers CA, Allison JP (1999) CTLA, the costimulatory molecule that doesn’t: regulation of T-cell responses by inhibition. Cold Spring Harb Symp Quant Biol 64:303–312
Chambers CA, Kuhns MS, Egen JG, Allison JP (2001) CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19:565–594
Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736
Pentcheva-Hoang T, Egen JG, Wojnoonski K et al (2004) B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 21:401–413
Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182:459–465
Newton Bishop JA (1997) Molecular pathology of melanoma. Cancer Metastasis Rev 16:141–154
Hodi S, Mihm MC, Soiffer RJ et al (2003) Biologic activity of cytotoxic T lymphocyte antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 100(8):4712–4717
Phan GQ, Yang JC, Sherry RM et al (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377
Attia P, Phan GQ, Maker AV et al (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23:6043–6053
Weber JS, Hersh EM, Yellin M et al (2007) The efficacy and safety of ipilimumab (MDX-010) in patients with unresectable stage III or stage IV malignant melanoma. J Clin Oncol suppl 25: abstr 8523
Weber J, O’Day S, Urba W (2008) Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 26(36):5950–5956
Fischkoff SA, Hersh E, Weber J et al (2005) Durable responses and long-term progression-free survival observed in a phase II study of MDX-010 alone or in combination with dacarbazine (DTIC) in metastatic melanoma. J Clin Oncol, ASCO annual meeting proceedings 23 June, suppl 1: 7525
Hersh EM, Weber JS, Powderly JD et al (2008) Disease control and long-term survival in chemotherapy-naïve patients with advanced melanoma treated with ipilimumab (MDX-010) with or without dacarbazine. J Clin Oncol suppl 26: abstr 9022
Downey SG, Klapper JA, Smith FO et al (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated with CTL-associated 4 blockade. Clin Cancer Res 13:6681–6688
Maker AV, Yang JC, Sherry RM et al (2006) Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother 29:455–463
Hamid O, Chin K, Li J et al (2008) Dose effect of ipilimumab in patients with advanced melanoma: results from a phase II, randomized, dose-ranging study. J Clin Oncol suppl 26: abstr 9025
Weber JS, Berman D, Siegel J et al (2008) Safety and efficacy of ipilimumab with or without prophylactic budesonide in treatment-naive and previously treated patients with advanced melanoma. J Clin Oncol ASCO annual meeting proceedings, Part I, 26 May suppl 20: abstr 9010
Beck KE, Blansfield JA, Tran KQ et al (2006) Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 24:2283–2289
Blansfield JA, Beck KA, Tran K et al (2005) Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 28:593–598
Sanderson K, Scotland R, Lee P et al (2005) Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol 23:741–750
Weber J (2007) Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist 12:864–872
Weber JS, Targan S, Scotland R et al (2006) Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multipeptide vaccine for resected stages IIIC and IV melanoma. J Clin Oncol, ASCO annual meeting proceedings, Part I, 24 June 20, suppl 2510
Urba WJ, Weber JS, O’Day SJ et al (2008) Long-term survival of patients with advanced melanoma who received ipilimumab administered at 10 mg/kg every 3 weeks for 4 doses (induction dosing). J Clin Oncol suppl 26: abstr 3018
Hamid O, Urba WJ, Yellin M et al (2007) Kinetics of response to ipilimumab (MDX-010) in patients with stage III/IV melanoma. J Clin Oncol suppl 25: abstr 8525
Hodi FS, Hoos A, Ibrahim R et al (2008) Novel efficacy criteria for antitumor activity to immunotherapy using the example of ipilimumab, an anti-CTLA-4 monoclonal antibody. J Clin Oncol suppl 26: abstr 3008
Saenger YM, Wolchok JD (2008) The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Cancer Immun 8:1
Wolchok JD, Ibrahim R, DePril V et al (2008) Antitumor response and new lesions in advanced melanoma patients on ipilimumab treatment. J Clin Oncol suppl 26: abstr 3020
O’Day SJ, Ibrahim R, DePril V et al (2008) Efficacy and safety of ipilimumab induction and maintenance dosing in patients with advanced melanoma who progressed on one or more prior therapies. J Clin Oncol suppl 26: abstr 9021
Hodi FS, Butler M, Oble DA et al (2008) Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci USA 105(8):3005–3010
Chambers CA, Sullivan TJ, Allison JP (1997) Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7:885–895
Wing K, Onishi Y, Prieto-Martin P et al (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275
Maker AV, Attia P, Rosenberg SA (2005) Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 175(11):7746–7754
Ménard C, Ghiringhelli F, Roux S et al (2008) CTLA-4 blockade confers lymphocyte resistance to regulatory T-cells in advanced melanoma: surrogate marker of efficacy of tremelimumab? Clin Cancer Res 14(16):5242–5249
Liakou CI, Kamat A, Tang DN et al (2008) CTLA-4 blockade increases IFNgamma-producing CD4+ ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci USA 105(39):14987–14992
Breunis WB, Tarazona-Santos E, Chen R et al (2008) Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade. J Immunother 31(6):586–590
Acknowledgments
JW is a consultant for and receives research funding from Medarex and Bristol-Myers Squibb; JW is also a consultant for Pfizer.
Author information
Authors and Affiliations
Corresponding author
Additional information
This paper is a focussed research review based on a presentation given at the sixth annual meeting of the Association for Immunotherapy of Cancer (CIMT), held in Mainz, Germany, 15–16 May 2008.
Rights and permissions
About this article
Cite this article
Weber, J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother 58, 823–830 (2009). https://doi.org/10.1007/s00262-008-0653-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-008-0653-8