TLR5 enhancement of liver-directed radiotherapy plus immune checkpoint blockade against irradiated liver metastasis and abscopal tumors

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The liver is a frequent site of metastasis for several cancers and when this occurs, it is associated with poor response to immunotherapy. Liver-directed radiotherapy (RT) is a non-traditional immune modulating therapy that improves immune checkpoint blockade (ICB, αPD-1 or αPD-1/αCTLA-4) mediated control of liver metastasis and non-irradiated abscopal tumors. Unfortunately, enhanced tumor control following liver-directed radiotherapy and ICB is often short-lived for irradiated tumors and unpredictable for non-irradiated tumors. Thus, novel immunotherapeutic approaches that can stimulate antitumor immunity in the liver have the potential to boost liver-directed RT plus ICB mediated control of irradiated and non-irradiated abscopal tumors. Toward this goal, we are harnessing the ability of the toll-like receptor (TLR) 5 pathway to signal in the liver more so than other sites. Hepatocytes sense Salmonella flagellin and our derivative called entolimod through cell surface TLR5 and cytoplasmic NAIP5 inflammasome. Importantly, systemically administered entolimod was shown to be safe in rodents, non-human primates, and Phase I safety trials in healthy volunteers and cancer patients cumulatively involving nearly 200 subjects. Our prior work showed that entolimod protects normal tissues but not tumors from radiation toxicities and stimulates CD8+ T cell dependent antitumor immunity against preclinical models of liver metastasis. Here, we showed that entolimod enhances liver-directed RT in pre-clinical models mirroring advanced liver metastasis and that this occurs via a poorly resolved Nφ dependent mechanism. The outstanding questions that this proposal seeks to address are: 1) what is the impact of entolimod on liver-directed RT plus ICB mediated control of liver metastasis and abscopal tumors?; 2) how does the TLR5-NAIP5 pathway in Nφ support antitumor immunity post liver-directed RT and ICB?; and 3) what is the translational relevance of the TLR5-NAIP5 pathway plus RT in human tumors and Nφ? Our central hypothesis is that entolimod enhances liver-directed RT plus ICB via Nφ-dependent release of IFN-γ, a cytokine that can be released by activated Nφ to support antitumor immunity. To test our central hypothesis, we propose three interactive aims: 1) To unveil the impact of entolimod on liver-directed RT plus ICB mediated control of liver metastasis and abscopal tumors; 2) To elucidate the mechanism by which the TLR5-NAIP5 pathway in Nφ triggers antitumor immunity post liver- directed RT and ICB; and 3) To determine the translational relevance of the TLR5-NAIP5 pathway plus RT in fresh human colorectal cancer and melanoma samples and patient-matched Nφ. The impact of this work lies in the fact that all components of this therapy are in the clinic for cancer patients thereby ensuring the feasibility to combine these components into a novel and innovative therapy to improve the dire survival outcomes associated with liver metastasis.