# "Combining radiation with TLR5 agonist based immunotherapy against liver metastases"

> **NIH NIH R21** · ROSWELL PARK CANCER INSTITUTE CORP · 2020 · $189,986

## Abstract

Summary
 The long term goal of this research is to utilize toll-like receptor 5 (TLR5) agonist based immunotherapy
with immunomodulatory radiation treatment in the development of a safe and effective combinatorial approach
to control liver metastatic disease. The objective of this project is to demonstrate improved therapeutic efficacy
against liver metastatic disease using this novel treatment approach and to provide a mechanistic foundation to
advance further development of the combined strategy. The hypothesis underlying this research is that TLR5
agonist mediated immune response in the normal liver microenvironment combined with the
immunomodulatory effects of liver radiation treatment (RT) generate potent antitumor immunity to eliminate
liver metastases. This theory is based on recent cumulative data indicating that the liver microenvironment
possesses a unique character in which TLR5 agonists elicit a significant antitumor immune response mediated
by TLR5 responsive hepatocytes and on pilot experiments illustrating that the immune stimulatory effects of
ionizing radiation applied to the liver enhance and extend the therapeutic reach of TLR5 agonist
immunotherapy against liver metastases. In this project, the hypothesis will be tested using the highly
aggressive murine colorectal cancer and uveal melanoma liver metastasis models and the newly generated
and pharmacologically optimized TLR5 agonist, entolimod. The research plan includes testing different
combination therapy regimens and comparing the results of their application to that of liver radiation and TLR5
stimulation individually for antitumor efficacy against liver metastatic growth using the experimental colorectal
cancer and spontaneous uveal melanoma liver metastasis models (Aim 1). Single dose and fractionated RT
will be applied at different times (adjuvant and neoadjuvant) relative to systemic entolimod administration to
determine the most efficacious regimens of the combined therapy. The role of the immunological changes in
the hepatic microenvironment in the development of an efficacious antitumor immune response will be
determined using phenotypic and functional assays (Aim 2). The results will further the development of a
clinical protocol for this innovative approach. While the murine colorectal cancer and uveal melanoma liver
metastasis models were chosen due to the significant medical need, clear translational path and encouraging
preliminary results obtained with these models, the results will provide information relevant to other cancers
with a high propensity to metastasize to the liver. Completion of this project will provide supporting pre-clinical
efficacy data to facilitate advancement to clinical trials and a mechanistic foundation on which to base further
investigation of the molecular mechanisms responsible for the antitumor activity of this innovative therapeutic
approach that is critically needed against liver metastasis.

## Key facts

- **NIH application ID:** 9941064
- **Project number:** 5R21CA226463-02
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** ANDREI V GUDKOV
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $189,986
- **Award type:** 5
- **Project period:** 2019-06-03 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941064

## Citation

> US National Institutes of Health, RePORTER application 9941064, "Combining radiation with TLR5 agonist based immunotherapy against liver metastases" (5R21CA226463-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9941064. Licensed CC0.

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