Journal Article
. 2014 Apr; 1(4):229-34.
doi: 10.1158/2326-6066.CIR-13-0020.

Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy

Derek Ng Tang 1 Yu Shen  Jingjing Sun  Sijin Wen  Jedd D Wolchok  Jianda Yuan  James P Allison  Padmanee Sharma  
  • PMID: 24777852
  •     26 References
  •     87 citations


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.

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Oncoimmunology, 2021 Apr 03; 10(1). PMID: 33796406    Free PMC article.
Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer.
Colt Egelston, Weihua Guo, +9 authors, Yuan Yuan.
J Immunother Cancer, 2021 Mar 25; 9(3). PMID: 33757987    Free PMC article.
Recruitment and Expansion of Tregs Cells in the Tumor Environment-How to Target Them?
Justine Cinier, Margaux Hubert, +5 authors, Christine Ménétrier-Caux.
Cancers (Basel), 2021 May 01; 13(8). PMID: 33924428    Free PMC article.
Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer.
Meenal Sinha, Li Zhang, +14 authors, Lawrence Fong.
J Immunother Cancer, 2021 May 15; 9(5). PMID: 33986125    Free PMC article.
Trough levels of ipilimumab in serum as a potential biomarker of clinical outcomes for patients with advanced melanoma after treatment with ipilimumab.
Yoshinobu Koguchi, Noriko Iwamoto, +6 authors, William L Redmond.
J Immunother Cancer, 2021 Oct 09; 9(10). PMID: 34620702    Free PMC article.
Pilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma.
Matthew T Campbell, Surena F Matin, +19 authors, Padmanee Sharma.
Nat Commun, 2021 Nov 06; 12(1). PMID: 34737281    Free PMC article.
Combining CTLA-4 and angiopoietin-2 blockade in patients with advanced melanoma: a phase I trial.
Patrick A Ott, Matthew Nazzaro, +12 authors, F Stephen Hodi.
J Immunother Cancer, 2021 Nov 14; 9(11). PMID: 34772758    Free PMC article.
Our current understanding of checkpoint inhibitor therapy in cancer immunotherapy.
Elena Goleva, Taras Lyubchenko, +3 authors, Jeffrey A Kern.
Ann Allergy Asthma Immunol, 2021 Mar 16; 126(6). PMID: 33716146    Free PMC article.
A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance.
Alexander C Huang, Roberta Zappasodi.
Nat Immunol, 2022 Mar 05; 23(5). PMID: 35241833    Free PMC article.
Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma.
Maria Davern, Noel E Donlon, +14 authors, Joanne Lysaght.
Transl Oncol, 2022 Apr 03; 20. PMID: 35366537    Free PMC article.