Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 39, Pages 14987-14992Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806075105
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Funding
- Physician-Scientist Program
- Institutional Research Grant from the University of Texas
- Anderson Cancer Center
- American Society of Clinical Oncology
- Bristol-Myers Squibb
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Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent antiCTLA-4 antibody. All clinical trials to date, comprising over 3,000 patients, have been conducted in the metastatic disease setting, which allows for correlation of drug administration with clinical outcome but has limited analyses of intermediate biomarkers to indicate whether the drug has impacted human immune responses within the tumor microenvironment. We conducted a pre-surgical clinical trial in six patients with localized bladder cancer, which allowed for correlation of drug administration with biomarkers in both blood and tumor tissues but did not permit correlation with clinical outcome. We found that CD4 T cells from peripheral blood and tumor tissues of all treated patients had markedly increased expression of inducible costimulator (ICOS). These CD4(+) ICOShi T cells produced IFN-gamma (IFN gamma) and could recognize the tumor antigen NY-ESO-1. Increase in CD4(+) ICOShi cells led to an increase in the ratio of effector to regulatory T cells. To our knowledge, these are the first immunologic changes reported in both tumor tissues and peripheral blood as a result of treatment with anti-CTLA-4 antibody, and they may be used to guide dosing and scheduling of this agent to improve clinical responses.
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