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Journal of Translational Medicine

, 9:204

First Online: 28 November 2011Received: 14 December 2010Accepted: 28 November 2011DOI: 10.1186-1479-5876-9-204

Cite this article as: Hamid, O., Schmidt, H., Nissan, A. et al. J Transl Med 2011 9: 204. doi:10.1186-1479-5876-9-204


BackgroundIpilimumab, 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.

MethodsIn 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.

ResultsObjective 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.

ConclusionsBaseline 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.

KeywordsCytotoxic T-lymphocyte antigen-4 FoxP3 indoleamine 2,3-dioxygenase ipilimumab melanoma tumor biomarker tumor-infiltrating lymphocytes Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-9-204 contains supplementary material, which is available to authorized users.

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Autor: Omid Hamid - Henrik Schmidt - Aviram Nissan - Laura Ridolfi - Steinar Aamdal - Johan Hansson - Michele Guida - David M Hy

Fuente: https://link.springer.com/

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