Abstract LB-160: Dual application of TLR5 agonist in cancer treatment: A single agent combines supporting care and antitumor activities

We have previously shown the strong radioprotective properties of TLR5 agonist flagellin in both mouse and non-human primate models (Burdelya et al., 2008, Science 320: 226–230). A pharmacologically optimized flagellin derivative, Protectan CBLB502, is currently at an advanced stage of development as a prospective radiation antidote for biodefense applications. 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. For example, injections of CBLB502 significantly reduced the severity of mucositis and dermatitis associated with local fractioned irradiation of the head and neck area of mice with syngeneic orthotopically grown head and neck carcinoma with no reduction of antitumor effect of experimental radiotherapy. On the contrary, use of CBLB502 led to enhanced tumor suppression by radiation and produced a detectable tumor suppressive effect even without irradiation. Similar results were obtained in s.c. grown syngeneic colon Wart tumors in rats. In this model, administration of CBLB502 reduced the severity of irinotecan-induced diarrhea, but did not interfere with the anti-tumor effect of the drug. Moreover, use of CBLB502 as a single agent had a pronounced antitumor effect in the majority of Wart tumor-carrying rats. 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 growing as experimental metastases in the liver which was found to be the primary target of TLR5 agonist. The liver responds to CBLB502 injection by massive and rapid activation of NF-kB in all hepatocytes. This results in dramatic changes in the content of secreted factors, attraction of immunocytes and a strong reversible increase in liver resistance to a variety of toxic agents. Based on these results, we project clinical applications of CBLB502 as a bi-functional therapeutic agent with supporting care (protection of normal tissues from radio- and chemotherapy side effects) and immunotherapeutic activities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-160. doi:10.1158/1538-7445.AM2011-LB-160