# The Role of Tumor-Targeted TLR5 Activation in Reversing Immune Checkpoint Therapy Resistance

> **NIH NIH F30** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $33,541

## Abstract

PROJECT SUMMARY/ABSTRACT
Immune checkpoint therapies (ICTs) demonstrate the exciting efficacy of therapies that modulate the immune
system to combat cancer. Compared to traditional chemotherapeutic strategies, which typically extend overall
survival by a few months, ICTs can lead to durable anti-cancer responses that increase overall patient survival
by years or more. However, 60-80% of patients are unresponsive to ICTs and new therapeutic strategies are
necessary to treat these ICT-resistant tumors. ICTs modulate the adaptive immune system by acting on T cells.
Agonists of toll like receptors (TLRs) act on the innate immune system and are an underexplored mechanism by
which to drive an anti-cancer immune response. TLR5 agonists have been shown to be tolerable when
administered subcutaneously and intravenously in clinical trials and flagellin, a TLR5 agonist, has demonstrated
potent anti-tumor effects in animal models when administered by intra-tumoral injection. In addition, preliminary
data has shown that intra-tumoral injection of flagellin can overcome ICT resistance and this effect is due to local
modulation of the tumor immune microenvironment (TIME). However, as not all patient tumors are accessible
by direct injection, new methodologies are needed to formulate and deliver flagellin as an anti-cancer therapeutic.
As such, this proposal is focused on the development of a novel method to deliver flagellin directly to the tumor
compartment and understanding the mechanisms by which tumor-targeted TLR5 activation overcomes ICT
resistance. The central hypothesis of this proposal is that tumor-targeted activation of TLR5 of the TIME, via NF-
κB signaling, will reprogram PMN-MDSCs in the TIME, relieving T cell suppression to overcome ICT resistance.
This hypothesis will be investigated in the following aims. In Aim 1, the bio-distribution and pharmacokinetics of
tumor-targeted delivery of flagellin will be assessed by PET. In Aim 2, the therapeutic efficacy of tumor-targeted
TLR5 activation will be assessed as a standalone agent or in combination with ICT by treating ICT-resistant
tumors. Finally, Aim 3 will investigate, the mechanisms by which tumor-targeted TLR5 activation reprograms
PMN-MDSCs in the TIME to overcome ICT resistance. Understanding the mechanisms by which TLR5 activation
can overcome ICT resistance and developing a mechanism to deliver flagellin directly to tumors will provide
novel methodologies to combat ICT resistance and develop readily translatable therapeutics for patients with
ICT-resistant tumors. In addition, completion of this proposal by the applicant at the MD Anderson Cancer Center
in the Department of Cancer Systems Imaging will provide the applicant with exceptional training opportunities
in cancer immunology and imaging, as well as enhance the applicant's training goals of becoming an
independent investigator.

## Key facts

- **NIH application ID:** 10090450
- **Project number:** 5F30CA239332-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Sarah E Glazer
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,541
- **Award type:** 5
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090450

## Citation

> US National Institutes of Health, RePORTER application 10090450, The Role of Tumor-Targeted TLR5 Activation in Reversing Immune Checkpoint Therapy Resistance (5F30CA239332-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10090450. Licensed CC0.

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