An immune-active tumor microenvironment favors clinical response to ipilimumab.

Abstract

PURPOSE:

Ipilimumab, a fully human monoclonal antibody specific to CTLA-4, has been shown to improve overall survival in metastatic melanoma patients. As a consequence of CTLA-4 blockade, ipilimumab treatment is associated with proliferation and activation of peripheral T cells. To better understand various tumor-associated components that may influence the clinical outcome of ipilimumab treatment, gene expression profiles of tumors from patients treated with ipilimumab were characterized.

EXPERIMENTAL DESIGN:

Gene expression profiling was performed on tumor biopsies collected from 45 melanoma patients before and 3 weeks after the start of treatment in a phase II clinical trial.

RESULTS:

Analysis of pre-treatment tumors indicated that patients with high baseline expression levels of immune-related genes were more likely to respond favorably to ipilimumab. Furthermore, ipilimumab appeared to induce two major changes in tumors from patients who exhibited clinical activity: genes involved in immune response showed increased expression, whereas expression of genes for melanoma-specific antigens and genes involved in cell proliferation decreased. These changes were associated with the total lymphocyte infiltrate in tumors, and there was a suggestion of association with prolonged overall survival in these patients. Many IFN-γ-inducible genes and Th1-associated markers showed increased expression after ipilimumab treatment, suggesting an accumulation of this particular type of T cell at the tumor sites, which might play an important role in mediating the antitumor activity of ipilimumab.

CONCLUSIONS:

These results support the proposed mechanism of action of ipilimumab, suggesting that cell-mediated immune responses play an important role in the antitumor activity of ipilimumab.

• Authors: Rui-Ru Ji, Scott D Chasalow, Lisu Wang, Omid Hamid, Henrik Schmidt, John Cogswell, Suresh Alaparthy, David Berman, Maria Jure-Kunkel, Nathan O Siemers, Jeffrey R Jackson, Vafa Shahabi
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 61 Issue 7 Pg. 1019-31 (Jul 2012) ISSN: 1432-0851 [Electronic] Germany
• PMID: 22146893 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Ipilimumab

Topics

• Antibodies, Monoclonal (immunology, therapeutic use)
• Antineoplastic Agents (immunology, therapeutic use)
• Biopsy
• Gene Expression (drug effects)
• Gene Expression Profiling
• Humans
• Ipilimumab
• Lymphocytes, Tumor-Infiltrating (immunology)
• Melanoma (drug therapy, genetics, immunology, pathology)
• Neoplasm Metastasis
• Neoplasm Staging
• Skin Neoplasms (drug therapy, genetics, immunology, pathology)
• Survival Analysis
• Tumor Microenvironment (immunology)