Abstract 4398: Liver is a major primary target for the Toll-like receptor-5 agonist CBLB502 providing radioprotective, antimicrobial and antitumor responses

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL We have previously shown that activation of Toll-like receptor 5 (TLR5) by bacterial flagellin and by pharmacologically optimized flagellin derivative CBLB502 protects mice and monkeys from lethal radiation injury to the hematopoietic and gastrointestinal systems. Here, we report that the liver is a major primary CBLB502 target organ in mice, with hepatocytes specifically showing rapid and strong NF-kB and STAT3 activation. Livers from CBLB502-treated mice showed up-regulation of numerous downstream genes encoding intracellular and secreted proteins with anti-apoptotic, anti-microbial and immunomodulatory activities. Unlike the TLR4 agonist LPS, the liver response to TLR5 agonists appears to be direct and does not involve high levels of proinflammatory cytokines. Thus, while LPS is toxic, TLR5 agonists have strong clinical potential. The importance of liver for CBLB502 radioprotective activity was confirmed by temporary occlusion of liver blood circulation which completely abrogated the protective effect of CBLB502 on hematopoietic precursor cells in irradiated mice. CBLB502 also protected liver tissue itself, increasing mouse resistance to lethal Salmonella tiphymurium liver infection and to hepatotoxic Fas agonistic antibodies. By testing CBLB502 in combination with radiation treatment of experimental mouse tumors in vivo, we demonstrated that its tissue protection properties are limited to normal tissues with no tumor protection detected in any of numerous mouse tumor models. Moreover, direct antitumor effects of CBLB502 treatment was observed in several tumor models. Comparison of the effect of CBLB502 on in vivo growth of isogenic pairs of tumor cell lines differing in their TLR5 status showed that the antitumor effect of the TLR5 agonist is TLR5 dependent and is associated with tumor infiltration by immunocytes, presumably attracted following activation of TLR5 signaling in the tumor cells. Remarkably, CBLB502 caused an immunotherapeutic effect in TLR5-negative tumors (CT26 colon adenocarcinoma and A20 lymphoma) growing as experimental liver metastases. Based on these results, we project clinical applications of CBLB502 as an anticancer immunotherapeutic drug against liver metastases independently on TLR5 status and TLR5-expressing tumors in other locations as well as supporting care drug to reduce adverse hepatotoxicity from radiation and chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4398. doi:1538-7445.AM2012-4398