Entolimod, a clinical-stage TLR5 agonist, activates antitumor T cell immunity against liver and lung metastases through distinct mechanisms

Abstract

Innate immune modulators can generate an antitumor T cell response. However, significant toxicities associated with systemic administration have significantly limited their clinical use. The natural TLR5 agonist flagellin is unique amonginnate immune modulators because the tissue specificity of TLR5 expression induces a uniquely safe profile of cytokines following systemic TLR5 activation. Entolimod, a pharmacologically optimized flagellin derivative, was initially developed to treat and prevent acute radiation syndrome. Systemic administration of entolimod also showed antitumor effects in multiple preclinical mouse models mimicking clinically occurring liver metastasis. Entolimod suppresses liver metastasis through activation of NF-κB-, AP-1-, and STAT-3-driven immunomodulatory pathways in hepatocytes and a highly coordinated CD4⁺ T cell independent NK-DC-CD8⁺ T cell response. Although these studies characterized entolimod as a liver tropic immunotherapy, entolimod also suppresses spontaneous mammary lung metastasis. In contrast to the liver metastatic model, CD4⁺ T cells are required for the antitumor NK and CD8⁺ T cell response, indicating that the etiology of the cancer may explain the difference in the therapeutic effects ofTLR5 agonists. These results further strengthen that TLR5 agonists are a safe, effective and broadly applicable immunotherapeutic agent against 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 provided the rationale to test that the efficacy demonstrated in animal cancer models can be translated into immunotherapy of human tumors.