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

Omid Hamid1*, Henrik Schmidt2, Aviram Nissan3, Laura Ridolfi4, Steinar Aamdal5, Johan Hansson6, Michele Guida7, David M Hyams8, Henry Gómez9, Lars Bastholt10, Scott D Chasalow11 and David Berman12

Author Affiliations

1 Melanoma Center, The Angeles Clinic and Research Institute, (2001 Santa Monica Blvd), Santa Monica, (90404), USA

2 Department of Clinical Medicine and Department of Oncology, Aarhus University Hospital, (Nørrebrogade 44), Aarhus C, (DK-8000), Denmark

3 Department of Surgery, Hadassah Hebrew University Medical Center, (P.O.Box 24035), Jerusalem, (il-91240), Israel

4 Immunotherapy Unit, IRST Cancer Institute, (Via P. Maroncelli 40) Meldola, (47014), Italy

5 Department of Oncology, Section for Clinical Cancer Research, Oslo University Hospital, (Ullernchausseen 70, OUS Radiumhospitalet), Oslo, (0310), Norway

6 Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, (SE-171), Stockholm, (77), Sweden

7 Department of Medical Oncology, National Institute of Cancer, (Viale Orazio Flacco 65), Bari, (70124), Italy

8 Desert Surgical Oncology, (39000 Bob Hope Drive), Rancho Mirage, (92270), USA

9 Department of Medicine, Instituto Nacional de Enfermedades Neoplásicas, (Avenida Angamos, Este 2520), Lima (34), Perú

10 EORTC Melanoma Group, Odense University Hospital, (Sdr. Boulevard 29), Odense, (DK-5000), Denmark

11 Exploratory Development, Global Biometric Sciences, Bristol-Myers Squibb Company, (Route 206 & Province Line Rd), Princeton, (08543), USA

12 Research and Development, Discovery Medicine, Bristol-Myers Squibb Company, (Route 206 & Province Line Rd), Princeton, (08543), USA

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Journal of Translational Medicine 2011, 9:204  doi:10.1186/1479-5876-9-204

Published: 28 November 2011



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.


In this randomized, double-blind, phase II biomarker study ( 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.


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.


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.

Cytotoxic T-lymphocyte antigen-4; FoxP3; indoleamine 2,3-dioxygenase; ipilimumab; melanoma; tumor biomarker; tumor-infiltrating lymphocytes