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

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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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Most cited references 38

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THE USE OF CONFIDENCE OR FIDUCIAL LIMITS ILLUSTRATED IN THE CASE OF THE BINOMIAL

C. J. CLOPPER, E. PEARSON (1934)

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Effector memory T cells, early metastasis, and survival in colorectal cancer.

Franck Pagès, Anne Berger, Matthieu Camus … (2005)

The role of tumor-infiltrating immune cells in the early metastatic invasion of colorectal cancer is unknown. We studied pathological signs of early metastatic invasion (venous emboli and lymphatic and perineural invasion) in 959 specimens of resected colorectal cancer. The local immune response within the tumor was studied by flow cytometry (39 tumors), low-density-array real-time polymerase-chain-reaction assay (75 tumors), and tissue microarrays (415 tumors). Univariate analysis showed significant differences in disease-free and overall survival according to the presence or absence of histologic signs of early metastatic invasion (P<0.001). Multivariate Cox analysis showed that an early conventional pathological tumor-node-metastasis stage (P<0.001) and the absence of early metastatic invasion (P=0.04) were independently associated with increased survival. As compared with tumors with signs of early metastatic invasion, tumors without such signs had increased infiltrates of immune cells and increased levels of messenger RNA (mRNA) for products of type 1 helper effector T cells (CD8, T-BET [T-box transcription factor 21], interferon regulatory factor 1, interferon-gamma, granulysin, and granzyme B) but not increased levels of inflammatory mediators or immunosuppressive molecules. The two types of tumors had significant differences in the levels of expression of 65 combinations of T-cell markers, and hierarchical clustering showed that markers of T-cell migration, activation, and differentiation were increased in tumors without signs of early metastatic invasion. The latter type of tumors also had increased numbers of CD8+ T cells, ranging from early memory (CD45RO+CCR7-CD28+CD27+) to effector memory (CD45RO+CCR7-CD28-CD27-) T cells. The presence of high levels of infiltrating memory CD45RO+ cells, evaluated immunohistochemically, correlated with the absence of signs of early metastatic invasion, a less advanced pathological stage, and increased survival. Signs of an immune response within colorectal cancers are associated with the absence of pathological evidence of early metastatic invasion and with prolonged survival. Copyright 2005 Massachusetts Medical Society.

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The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine.

Jeffrey Ross, Elzbieta Slodkowska, W Symmans … (2009)

The human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization, are presented and contrasted in detail against the background of the published American Society of Clinical Oncology-College of American Pathologists guidelines for HER-2 testing. Testing issues, such as the impact of chromosome 17 polysomy and local versus central HER-2 testing, are also discussed. Emerging novel HER-2 testing techniques, including mRNA-based testing by real-time polymerase chain reaction and DNA microarray methods, HER-2 receptor dimerization, phosphorylated HER-2 receptors, and HER-2 status in circulating tumor cells, are also considered. A series of biomarkers potentially associated with resistance to trastuzumab is discussed with emphasis on the phosphatase and tensin homologue deleted on chromosome ten/Akt and insulin-like growth factor receptor pathways. The efficacy results for the more recently approved small molecule HER-1/HER-2 kinase inhibitor lapatinib are also presented along with a more limited review of markers of resistance for this agent. Additional topics in this section include combinations of both anti-HER-2 targeted therapies together as well as with novel agents including bevacizumab, everolimus, and tenespimycin. A series of novel HER-2-targeting agents is also presented, including pertuzumab, ertumaxomab, HER-2 vaccines, and recently discovered tyrosine kinase inhibitors. Biomarkers predictive of HER-2 targeted therapy toxicity are included, and the review concludes with a consideration of HER-2 status in the prediction of response to non-HER-2 targeted treatments including hormonal therapy, anthracyclines, and taxanes.

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Author and article information

Journal

Journal ID (nlm-ta): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central

ISSN (Electronic): 1479-5876

Publication date Collection: 2011

Publication date (Electronic): 28 November 2011

Volume: 9

Page: 204

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

Article

Publisher ID: 1479-5876-9-204

DOI: 10.1186/1479-5876-9-204

PMC ID: 3239318

PubMed ID: 22123319

SO-VID: d8c061c0-ed38-4863-90c8-7ecd2bbcd9c8

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

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Karger: Dermatology

Most cited references 38

THE USE OF CONFIDENCE OR FIDUCIAL LIMITS ILLUSTRATED IN THE CASE OF THE BINOMIAL

Effector memory T cells, early metastasis, and survival in colorectal cancer.

The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine.

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