Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy Journal Article
| Authors: | Tang, D. N.; Shen, Y.; Sun, J. J.; Wen, S. J.; Wolchok, J. D.; Yuan, J. D.; Allison, J. P.; Sharma, P. |
| Article Title: | Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy |
| 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. (C)2013 AACR. |
| Keywords: | antibody; trial; metastatic melanoma; prostate-cancer; activation; ctla-4 blockade; combination immunotherapy; effector; cd28; stimulation |
| Journal Title: | Cancer Immunology Research |
| Volume: | 1 |
| Issue: | 4 |
| ISSN: | 2326-6066 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2013-10-01 |
| Start Page: | 229 |
| End Page: | 234 |
| Language: | English |
| ACCESSION: | WOS:000340030200005 |
| DOI: | 10.1158/2326-6066.cir-13-0020 |
| PROVIDER: | wos |
| PUBMED: | 24777852 |
| PMCID: | PMC4636341 |
| Notes: | Article -- Source: Wos |
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