A mouse GITRL fusion protein drives T-cell activation and antitumor activity in preclinical mouse models of cancer (Abstract only)

LEYLAND, Rebecca, WATKINS, Amanda, MULGREW, Kathy A, BAMBER, Lisa, TIGUE, Natalie J, DICK, Emily, HOLOWECKYJ, Nick, YOUNG, Lesley, MORROW, Michelle, HAMMOND, Scott A, LEOW, Ching Ching, WILKINSON, Robert W and STEWART, Ross (2016). A mouse GITRL fusion protein drives T-cell activation and antitumor activity in preclinical mouse models of cancer (Abstract only). Cancer Research, 76 (14 Sup), p. 4902.

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Abstract

GITR is a member of the TNFR superfamily of proteins and is expressed on resting regulatory T-cells and on other T-cells following activation. Signals through GITR have been shown to drive increased T-cell activity and reduced regulatory T-cell function. In order to explore the potential of therapeutically targeting GITR in a cancer setting, we generated a mouse GITRL fusion protein (mGITRL FP) consisting of the extracellular domain of mGITRL linked to a structural domain and an IgG Fc domain. The antitumor activity and pharmacodynamic effects of this molecule were then explored in the colorectal syngeneic model of cancer (CT26). Treatment of mice with mGITRL FP mediated anti-tumor activity that was dependent on isotype and exposure. The anti-tumor activity could be attributed at least in part to the increased activation and proliferation status of CD8+ and CD4+ T-cells, as evidenced by increases in Ki67 expression and ICOS upregulation. Intratumourally we observed a significant decrease in the frequency of CD4+ T-cells (including T regs), but a corresponding increase in cytotoxic CD8+ T-cells. OX40 is another member of the TNFR superfamily, that has similar expression and functions to GITR. In order to better understand the potential differences between targeting of these two pathways, the activity and pharmacodynamic effects of the mGITRL FP were additionally compared and contrasted to those of a mOX40L FP and the observed differences will be discussed.

Item Type:	Article
Uncontrolled Keywords:	1112 Oncology And Carcinogenesis; Oncology & Carcinogenesis
Identification Number:	https://doi.org/10.1158/1538-7445.AM2016-4902
Page Range:	p. 4902
SWORD Depositor:	Symplectic Elements
Depositing User:	Symplectic Elements
Date Deposited:	01 Apr 2019 15:22
Last Modified:	18 Mar 2021 05:49
URI:	https://shura.shu.ac.uk/id/eprint/23042

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