Liver metastases are a major common cause of mortality of patients with different types of cancer due to lack of effective treatment options. Anticancer immunotherapy provides an attractive approach for developing a more effective systemic therapy for patients with metastatic liver cancer. We generated a Toll-like receptor 5 (TLR5) agonistic agent entolimod™ (CBLB502), a pharmacologically optimized derivative of bacterial Salmonella flagellin that is now at advanced stage of clinical development as a medical countermeasure to reduce adverse side effects of radiation therapy. We also found that entolimod, in addition to its radioprotective properties, has anticancer effects against a variety of TLR5-positive tumors and TLR5-negative tumors residing in a TLR5-expressing environment such as the liver in mice. We hypothesized that entolimod can suppress tumor growth in a TLR5-responsive microenvironment such as the liver independently of the TLR5 status of tumor cells. We tested the therapeutic potential of entolimod against TLR5 responsive and non-responsive tumors using mouse triple negative 4T1 breast and CT26 colorectal adenocarcinoma models mimicking clinically occurring development of post-surgery liver metastases in cancer patients. Our results demonstrate that entolimod treatment was efficient in suppressing metastatic growth when injected systemically in both models. Investigating the mechanism of entolimod's antitumor activity we found that several major transcriptional factors, such as NF-κB, STAT-3 and AP-1, are rapidly activated in hepatocytes leading to a short-term neutrophilic infiltration and long-term NK cell accumulation and activation that coordinate CD8+ and CD4+ T cell immunity against liver metastases. This resulted in significant improvement of long-term tumor-free survival and durable, tumor-specific T cell memory. Importantly, unlike other TLR agonists entolimod is safe and does not show signs of septic shock even with systemic administration. Moreover, the results of two phase 1 clinical trials with 150 healthy volunteers and 26 patients with advanced cancers demonstrated good tolerability and safe profile of the response, which supports entolimod's potential as an immunotherapeutic agent. This also suggests that entolimod can be potentially combined with radiation, chemotherapeutic, targeted, and other immunotherapeutic agents to improve the efficacy of anticancer therapy.
Citation Format: Craig Brackett, Bojidar Kojouharov, Sandra Gollnick, Andrei Gudkov, Lyudmila Burdelya. A Toll-like receptor 5 agonist entolimod as a potential anticancer immunotherapeutic agent. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B090.
- ©2016 American Association for Cancer Research.