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We have previously identified a cellular protein kinase activity termed TAK that specifically associates with the HIV types 1 and 2 Tat

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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 performed 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: 88%-100%) and sensitivity of 71% (95% CI: 54%-85%), with positive expression defined as a frequency that is greater than the upper bound of 95% confidence interval 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.