Review of Immune-Related Adverse Events in Prostate Cancer Patients Treated with Ipilimumab: MD Anderson Experience

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Abstract

Targeting a T cell inhibitory checkpoint with the anti-CTLA-4 monoclonal antibody, ipilimumab, represents a scientific breakthrough in immunotherapy for the treatment of cancer. However, ipilimumab therapy is also associated with unique side effects, known as immune-related adverse events (irAEs), which need to be recognized and managed with immunosuppressive agents. To date, the majority of our knowledge regarding ipilimumab-associated side effects is based upon clinical studies in melanoma. Here, we provide a review of ipilimumab-induced irAEs and our experience in a cohort of 44 patients with prostate cancer who were treated at M. D. Anderson Cancer Center on two different clinical trial protocols.

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Most cited references 27

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Enhancement of antitumor immunity by CTLA-4 blockade.

D Leach, M. Krummel, J Allison (1996)

One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.

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Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.

Jedd Wolchok, Bart Neyns, Gerald P. Linette … (2010)

Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma. We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640. The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group). Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. Bristol-Myers Squibb. Copyright 2010 Elsevier Ltd. All rights reserved.

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Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.

Giao Phan, James Yang, Richard Sherry … (2003)

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to "self" antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.

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Author and article information

Journal

Journal ID (nlm-journal-id): 8711562

Journal ID (pubmed-jr-id): 6325

Journal ID (nlm-ta): Oncogene

Journal ID (iso-abbrev): Oncogene

Title: Oncogene

ISSN (Print): 0950-9232

ISSN (Electronic): 1476-5594

Publication date Nihms-submitted: 11 December 2014

Publication date (Electronic): 09 February 2015

Publication date (Print): October 2015

Publication date PMC-release: 01 April 2016

Volume: 34

Issue: 43

Pages: 5411-5417

Affiliations

[1 ]Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

[2 ]Department of Endocrine Neoplasia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

[3 ]Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

[4 ]Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

Author notes

[5 ]Corresponding author: Padmanee Sharma, MD, PhD, Departments of Genitourinary Medical Oncology and Immunology, 1155 Pressler Street, Unit 1374, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, PadSharma@ 123456mdanderson.org , Phone: 713-792-2830, Fax: 713-745-1625

Article

Manuscript ID: NIHMS647912

DOI: 10.1038/onc.2015.5

PMC ID: 4530091

PubMed ID: 25659583

SO-VID: 9b7d05ed-2a0c-4021-8654-9b84db456964

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Review of Immune-Related Adverse Events in Prostate Cancer Patients Treated with Ipilimumab: MD Anderson Experience

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Most cited references 27

Enhancement of antitumor immunity by CTLA-4 blockade.

Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.

Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.

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