TY - JOUR
T1 - CTLA-4 blockade increases IFNγ-producing CD4+ICOS hi cells to shift the ratio of effector to regulatory T cells in cancer patients
AU - Liakou, Chrysoula I.
AU - Kamat, Ashish
AU - Tang, Derek Ng
AU - Chen, Hong
AU - Sun, Jingjing
AU - Troncoso, Patricia
AU - Logothetis, Christopher
AU - Sharma, Padmanee
PY - 2008/9/30
Y1 - 2008/9/30
N2 - Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent anti-CTLA-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 (IFNγ) and could recognize the tumor antigen NY-ESO-1. Increase in CD4+ICOS hi 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.
AB - Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent anti-CTLA-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 (IFNγ) and could recognize the tumor antigen NY-ESO-1. Increase in CD4+ICOS hi 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.
UR - http://www.scopus.com/inward/record.url?scp=54449091476&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=54449091476&partnerID=8YFLogxK
U2 - 10.1073/pnas.0806075105
DO - 10.1073/pnas.0806075105
M3 - Article
C2 - 18818309
AN - SCOPUS:54449091476
SN - 0027-8424
VL - 105
SP - 14987
EP - 14992
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 39
ER -