An immune-active tumor microenvironment favors clinical response to ipilimumab
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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.
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.
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.
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.
KeywordsIpilimumab Metastatic melanoma Cytotoxic T lymphocyte antigen-4 Gene expression profiling Immunotherapy
We would like to thank Dr. Zenta Tsuchihashi for his contributions during design of the trial and initial data analysis, Drs. Julie Carman, Han Chang, Tai Wong, and Roumyana Yordanova for their guidance and critical review of the manuscript, and Ms. Beihong Hu and Aiqing He for technical support.
Conflict of interest
Rui-Ru Ji, Scott D. Chasalow, Lisu Wang, John Cogswell, Suresh Alaparthy, David Berman, Maria Jure-Kunkel, Nathan O. Siemers, Jeffrey R. Jackson, and Vafa Shahabi are employees of Bristol-Myers Squibb, the manufacturer of ipilimumab.
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