Activation of innate and adaptive immunity by a TLR5 agonist to prevent and suppress liver metastasis (TUM7P.947)

Colorectal cancer (CRC) liver metastases are a major cause of mortality of CRC patients providing incentive to develop systemic therapies to prevent and treat this condition. We are exploring the use of a TLR5 agonist Entolimod™ (CBLB502) for immunotherapy against CRC liver metastases. Entolimod is a pharmacologically optimized Salmonella flagellin derivative that is at advanced stage of clinical development as a medical radiation countermeasure. We found that liver is the major primary Entolimod target organ. Entolimod rapidly triggers a TLR5-elicited response in hepatocytes that activates NF-kB and quickly mobilizes immunity to the liver. This includes short-term neutrophilic infiltrate and long-term NK cell accumulation that coordinate CD8 and CD4 T cell immunity against CRC liver metastases. As a result, Entolimod administration dramatically improved long-term survival in a mouse model that mimicked clinically occurring development of post-surgery liver metastases in CRC patients. Importantly, Entolimod induces durable, tumor-specific T cell memory. Unlike other TLR agonists, systemic administration of Entolimod does not induce septic shock-like syndrome due to lack of production of cytokine storm-inducing cytokines upon TLR5 activation. These safe and long-lasting TLR5-elicited changes within liver provide important groundwork for further clinical development of Entolimod, which is currently in clinical trials as a potential immunotherapy against CRC liver metastases.