Abstract 5621: Prevalence of GITR expression and pharmacodynamic (PD) biomarkers in syngeneic tumor models treated by a GITR agonist (GITRL-Fc)

Autor: Gretchen Argast, Earth Light Lowe, Fiore Cattaruzza, John Lewicki, Pete Yeung, Min Wang, Ann M. Kapoun, Erwan LeScolan, Alayne Brunner, Belinda Cancilla, Gilbert O'Young, Yu-Wang Liu, Austin L. Gurney, Jennifer Cain, Tim Hoey, Rose Harris
Rok vydání: 2017
Předmět:
Zdroj: Cancer Research. 77:5621-5621
ISSN: 1538-7445
0008-5472
Popis: GITRL (Glucocorticoid-Induced Tumor Necrosis Factor Receptor Ligand, TNFSF18) is a member of the tumor necrosis factor (TNF) ligand superfamily. GITRL binds and activates the co-stimulatory surface receptor GITR, which promotes proliferation and activation of effector T cells (Teff) and inhibits suppressive activity of regulatory T cells (Treg). It is thus hypothesized that co-stimulation of GITR by agonist agents will promote anti-tumor immunity. We generated a novel single-gene GITRL trimer fused to an immunoglobulin Fc domain (GITRL-Fc) that shows robust single agent antitumor efficacy and immune effects in multiple syngeneic mouse models, suggesting its potential benefit in cancer immunotherapy To investigate the prevalence of GITR expression in human tumors, RNA-Seq data analyses of 33 tumor types in TCGA showed GITR is highly expressed in a subset of solid tumors, including head & neck, lung, breast, esophageal, and bladder cancers. In most solid tumors, GITR expression correlated poorly with T cell markers, implying that GITR may not be exclusive to immune cells and may be expressed in tumor cells as well. Similar findings emerged from RNA-Seq data analysis of patient-derived xenograft (PDX) samples from 24 tumor types. The gene expression data was corroborated by immunohistochemistry (IHC) analysis of GITR expression in 17 tumor types which showed that in addition to immune cells, GITR was expressed on tumor cell membranes. A multi-platform approach was taken to investigate GITRL-Fc pharmacodynamic (PD) biomarkers in tumors and in matched whole blood samples from mice bearing CT26 colon, 4T1 breast, and B16F10 melanoma carcinoma models. Global gene expression levels were profiled by microarray on treated and control tissues. We also monitored the changes of immune cell populations and cytokine secretions by flow cytometry, Luminex and IHC. Immune gene changes were more robust in tumors than in blood samples. In tumor samples, GITRL-Fc increased the gene expression associated with T cells, CD8 T cells, cytotoxicity, Th1 cells, interferon gamma (IFN-γ), natural killer cells, Teff cells, and T cell activation markers. These gene changes were validated by quantitative real-time PCR. Similarly, flow cytometry analysis showed that GITRL-Fc promoted activation of CD4+ effector cells, decreased Treg frequency, and increased the ratio of CD8+ T cell/Treg in the tumor. GITRL-Fc also modulated secretion of cytokines in splenocytes, including an increase in IFN-γ. Taken together, the PD biomarker changes in immune-related gene expression, immune cell populations, and cytokine secretions observed in these preclinical tumor models are consistent with GITRL-Fc mechanism of action and demonstrated target engagement of GITRL-Fc. Additional approaches, including in-silico sorting, to monitor rare immune cell populations in tumor samples will be discussed. Citation Format: Min Wang, Fiore Cattaruzza, Pete Yeung, Alayne Brunner, Erwan LeScolan, Yuwang Liu, Jennifer Cain, Gilbert OYoung, Earth Light Lowe, Belinda Cancilla, Rose Harris, Tim Hoey, Austin Gurney, John Lewicki, Gretchen Argast, Ann M. Kapoun. Prevalence of GITR expression and pharmacodynamic (PD) biomarkers in syngeneic tumor models treated by a GITR agonist (GITRL-Fc) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5621. doi:10.1158/1538-7445.AM2017-5621
Databáze: OpenAIRE
Externí odkaz: