Priority Brief Increased Frequency of ICOSþ CD4 T Cells as a Pharmacodynamic Biomarker

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 ICOSþ 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 immunomod-ulatory 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 ICOSþ 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 ICOSþ 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. Cancer Immunol Res; 1(4); 229–34. 2013 AACR