An Immune-Active Tumor Microenvironment Favors Clinical Response to Ipilimumab

Cancer Immunol Immunother. 2012 Jul;61(7):1019-31. doi: 10.1007/s00262-011-1172-6. Epub 2011 Dec 7.

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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

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

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Ipilimumab