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Published on: May 30, 2013
Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy
Derek Ng Tang1, Yu Shen, Jingjing Sun
1Authors' Affiliations: Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, New York.
Abstract:
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.
Insights
The frequency of inducible costimulator (ICOS)(+) CD4 T cells can serve as a reliable pharmacodynamic biomarker for anti-CTLA-4 therapy. This biomarker indicates the drug
Area of Science:
- Immunology
- Pharmacology
- Biomarker Discovery
Background:
- Pharmacodynamic biomarkers are crucial for assessing therapeutic agent efficacy by measuring target engagement and biological impact.
- A validated pharmacodynamic biomarker for anti-CTLA-4 therapy is needed to monitor treatment response.
- Previous research indicated that anti-CTLA-4 therapy elevates the frequency of CD4 T cells expressing inducible costimulator (ICOS).
Purpose of the Study:
- To evaluate the frequency of ICOS(+) CD4 T cells as a potential pharmacodynamic biomarker for anti-CTLA-4 therapy.
- To assess the reproducibility and reliability of this biomarker in patients receiving anti-CTLA-4 monoclonal antibody (mAb).
Main Methods:
- Flow cytometry was employed to quantify the frequency of ICOS(+) CD4 T cells.
- Statistical analyses were performed on data from 56 individuals, including healthy donors and patients treated with anti-CTLA-4 mAb (ipilimumab) or a gp100 DNA vaccine.
- Assay performance was evaluated for sensitivity and specificity after two doses of anti-CTLA-4 therapy.
Main Results:
- A statistically significant increase in the frequency of ICOS(+) CD4 T cells was observed following anti-CTLA-4 mAb treatment.
- The assay demonstrated high specificity (96%) and moderate sensitivity (71%) for detecting biologic activity.
- Positive expression was defined based on the upper bound of the 95% confidence interval of baseline samples.
Conclusions:
- Increased frequency of ICOS(+) CD4 T cells, measured by flow cytometry, is a reproducible pharmacodynamic biomarker for anti-CTLA-4 therapy.
- This biomarker can facilitate immune monitoring to assess adequate biologic response in patients undergoing anti-CTLA-4 treatment.
- The findings support the use of ICOS(+) CD4 T cell frequency for monitoring anti-CTLA-4 monotherapy and combination strategies.
