The clinical-stage TLR5 agonist, Entolimod, mediates antimetastatic activity by stimulating a CXCR3-dependent NK-DC-CD8+ T cell axis

Abstract

Abstract Activation of an anticancer innate immune response is an attractive immunotherapeutic opportunity that is challenged by insufficient safety of systemically administered innate immune modulators. Unusual tissue specificity of expression of TLR5 determines a uniquely safe profile of cytokines induced by the sole TLR5 agonist flagellin. Entolimod, a pharmacologically optimized flagellin derivative, was initially developed to treat and prevent acute radiation syndrome with demonstrated efficacy in rodents and non-human primates and safety in human healthy volunteers. In addition, Entolimod demonstrated antitumor effects in mouse models of uveal melanoma, lymphoma, breast, and colorectal carcinoma. Entolimod’s mechanism of action involves activation of NF-κB-, AP-1-, and STAT-3-driven immunomodulatory pathways in hepatocytes that initiates a cascade of cell-cell signaling events that mobilize innate and adaptive immunity to the liver. This includes CXCR3-dependent blood-borne NK cell homing followed by DC activation and antitumor CD8+ T cell memory formation. These results define systemically administered TLR5 agonists as an organ-specific immunoadjuvant enabling efficient antitumor vaccination that does not depend on identification of tumor-specific antigens. Therefore, Entolimod has strong promise as a safe, effective and broadly applicable immunotherapeutic agent against liver metastases, which are currently a major cause of cancer-associated mortality. Recent completion of a phase I trial of Entolimod in patients with advanced metastatic solid tumors has opened the opportunity to test whether efficacy demonstrated in animal cancer models could be translated into immunotherapy of human tumors.