Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy

Cancer Immunol Res. 2013 Oct;1(4):229-34. doi: 10.1158/2326-6066.CIR-13-0020. Epub 2013 Jul 31.


Pharmacodynamic biomarkers can play an important role in understanding whether a therapeutic agent has "hit its target" to impact biologic function. A pharmacodynamic biomarker for anti-CTLA-4 therapy remains to be elucidated. We previously reported that anti-CTLA-4 therapy increases the frequency of CD4 T cells expressing the inducible costimulator (ICOS) molecule. To determine whether the frequency of ICOS(+) CD4 T cells could be used as a pharmacodynamic biomarker for anti-CTLA-4 therapy, we carried out flow cytometric studies and statistical analyses on data from 56 individuals, which included 10 healthy donors, 36 patients who received anti-CTLA-4 monoclonal antibody (mAb), and 10 patients who received treatment with a different immunomodulatory agent (gp100 DNA vaccine). After treatment with anti-CTLA-4 mAb (ipilimumab; Bristol-Myers Squibb), we detected a statistically significant increase in the frequency of ICOS(+) CD4 T-cells. After two doses of anti-CTLA-4 therapy, the assay was found to have an estimated specificity of 96% [95% confidence interval (CI), 88-100] and sensitivity of 71% (95% CI, 54-85), with positive expression defined as a frequency that is more than the upper bound of 95% CI among baseline samples from all subjects. Our data suggest that an increased frequency of ICOS(+) CD4 T cells measured by flow cytometry can be used as a reproducible pharmacodynamic biomarker to indicate biologic activity in the setting of anti-CTLA-4 therapy, which should enable appropriate immune monitoring to determine whether patients receiving anti-CTLA-4 monotherapy or combination treatment strategies are having an adequate biologic response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / therapeutic use*
  • Biomarkers
  • CD4-Positive T-Lymphocytes / immunology*
  • CTLA-4 Antigen / immunology*
  • Cytokines / immunology
  • Flow Cytometry
  • Healthy Volunteers
  • Humans
  • Inducible T-Cell Co-Stimulator Protein / immunology*
  • Ipilimumab
  • Lymphocyte Activation / immunology*
  • Melanoma / drug therapy
  • Melanoma / immunology
  • Randomized Controlled Trials as Topic
  • Sensitivity and Specificity
  • Vaccines, DNA / therapeutic use


  • Antibodies, Monoclonal
  • Biomarkers
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cytokines
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • Ipilimumab
  • Vaccines, DNA