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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2011

Open Access 01-12-2011 | Research

A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

Authors: Omid Hamid, Henrik Schmidt, Aviram Nissan, Laura Ridolfi, Steinar Aamdal, Johan Hansson, Michele Guida, David M Hyams, Henry Gómez, Lars Bastholt, Scott D Chasalow, David Berman

Published in: Journal of Translational Medicine | Issue 1/2011

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Abstract

Background

Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.

Methods

In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.

Results

Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.

Conclusions

Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.
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Metadata
Title
A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma
Authors
Omid Hamid
Henrik Schmidt
Aviram Nissan
Laura Ridolfi
Steinar Aamdal
Johan Hansson
Michele Guida
David M Hyams
Henry Gómez
Lars Bastholt
Scott D Chasalow
David Berman
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2011
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-9-204

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