Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy.
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.
Authors' Affiliations: Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, New York.
Derek
D
Ng Tang
Yu
Y
Shen
Jingjing
J
Sun
Sijin
S
Wen
Jedd D
JD
Wolchok
Jianda
J
Yuan
James P
JP
Allison
Padmanee
P
Sharma
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D005434:Flow Cytometry; D064368:Healthy Volunteers; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology*; D000074324:Ipilimumab; D008213:Lymphocyte Activation / Q000276:immunology*; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology; D016032:Randomized Controlled Trials as Topic; D012680:Sensitivity and Specificity; D019444:Vaccines, DNA / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D000074324:Ipilimumab; D019444:Vaccines, DNA