Top

Published in:

01-05-2009 | Focussed Research Review

Ipilimumab: controversies in its development, utility and autoimmune adverse events

Author: Jeffrey Weber

Published in: Cancer Immunology, Immunotherapy | Issue 5/2009

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.

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 64:303–312PubMedCrossRef

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 19:565–594PubMedCrossRef

Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736PubMedCrossRef

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 21:401–413PubMedCrossRef

Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182:459–465PubMedCrossRef

Newton Bishop JA (1997) Molecular pathology of melanoma. Cancer Metastasis Rev 16:141–154PubMedCrossRef

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):4712–4717PubMedCrossRef

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 100:8372–8377PubMedCrossRef

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 23:6043–6053PubMedCrossRef

10.

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

11.

Weber J, O’Day S, Urba W (2008) Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 26(36):5950–5956PubMedCrossRef

12.

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

13.

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

14.

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 13:6681–6688PubMedCrossRef

15.

Maker AV, Yang JC, Sherry RM et al (2006) Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother 29:455–463PubMedCrossRef

16.

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

17.

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

18.

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 24:2283–2289PubMedCrossRef

19.

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 28:593–598PubMedCrossRef

20.

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 23:741–750PubMedCrossRef

21.

Weber J (2007) Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist 12:864–872PubMedCrossRef

22.

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

23.

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

24.

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

25.

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

26.

Saenger YM, Wolchok JD (2008) The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Cancer Immun 8:1PubMed

27.

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

28.

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

29.

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):3005–3010PubMedCrossRef

30.

Chambers CA, Sullivan TJ, Allison JP (1997) Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7:885–895PubMedCrossRef

31.

Wing K, Onishi Y, Prieto-Martin P et al (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275PubMedCrossRef

32.

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):7746–7754PubMed

33.

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):5242–5249PubMedCrossRef

34.

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):14987–14992PubMedCrossRef

35.

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):586–590PubMedCrossRef

Title: Ipilimumab: controversies in its development, utility and autoimmune adverse events
Author: Jeffrey Weber
Publication date: 01-05-2009
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 5/2009
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-008-0653-8

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2009

HER-2/neu mediated down-regulation of MHC class I antigen processing prevents CTL-mediated tumor recognition upon DNA vaccination in HLA-A2 transgenic mice

Report on the sixth annual meeting of the Association for Immunotherapy of Cancer (CIMT), May 15 and 16, 2008 in Mainz, Germany

Characterization of MHC class-I restricted TCRαβ+ CD4− CD8− double negative T cells recognizing the gp100 antigen from a melanoma patient after gp100 vaccination

Immunosensitization with a Bcl-2 small molecule inhibitor

Low-dose radiation enhances therapeutic HPV DNA vaccination in tumor-bearing hosts

Fit for purpose? A case study: validation of immunological endpoint assays for the detection of cellular and humoral responses to anti-tumour DNA fusion vaccines

Keynote webinar | Spotlight on antibody–drug conjugates in cancer