The Toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism
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Hua Yang1, Craig M. Brackett2, Vanessa Marie Morales-Tirado3, Zezhong Li1, Qing Zhang1, Matthew W. Wilson3, Camille Benjamin2, Wayne Harris4, Edmund K. Waller4, Andrei V. Gudkov2,5, Lyudmila G. Burdelya2, Hans E. Grossniklaus1
1Department of Ophthalmology, Emory University, Atlanta, GA, USA
2Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
3Department of Ophthalmology, Hamilton Eye Institute, The University of Tennessee Health Science Center, Memphis, TN, USA
4Deparment of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
5Cleveland BioLabs, Inc., Buffalo, NY, USA
Hans Grossniklaus, e-mail: [email protected]
Lyudmila Burdelya, e-mail: [email protected]
Keywords: TLR5, entolimod, uveal melanoma, liver metastases
Received: November 10, 2015 Accepted: November 23, 2015 Published: December 08, 2015
Uveal melanoma (UM) is the most common primary cancer of the eye in adults and progresses to metastatic disease predominantly of the liver in ~50% of patients. In these cases, life expectancy averages just 9 months due to the lack of effective treatment options. The Toll-like receptor 5 (TLR5) agonist entolimod (former name CBLB502) rapidly activates TLR5-NF-κB signaling in hepatocytes and suppresses growth of both TLR5-expressing and non-expressing tumors in the liver through mobilization and activation of innate and adaptive immune mechanisms. The goal of this study was to explore the potential of entolimod as an immunotherapeutic agent against hepatic metastasis of UM using the TLR5-positive B16LS9 mouse model of ocular melanoma. Mice were given seven subcutaneous injections of vehicle or entolimod given 72 h apart started one day before, on the same day or three days after intraocular injection of B16LS9 cells. All tested regimens of entolimod treatment resulted in significantly reduced B16LS9 metastasis to the liver. Entolimod induced mobilization of natural killer (NK) cells to the liver and stimulated their maturation, differentiation and activation. Antibody-mediated depletion of NK cells from mice abrogated entolimod's antimetastatic activity in the liver and eliminated the entolimod-elicited in vitro cytotoxic activity of hepatic lymphocytes against B16LS9 cells. These results provide pre-clinical evidence of entolimod's efficacy against hepatometastasis of UM and support its further development as an anticancer immunotherapeutic drug.
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