# Development of TLR5 agonist based approaches to boost chemo-immunotherapy by modulating immunosuppressive networks

> **NIH NIH R21** · ROSWELL PARK CANCER INSTITUTE CORP · 2022 · $235,901

## Abstract

ABSTRACT
Certain mouse and human cancers stimulate profound expansion of a type of highly immunosuppressive immune
cell called polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). These cells potently inhibit
antitumor immunity and thus remain a significant barrier to the efficacy of immunotherapy-based treatment
modalities for cancers that induce PMN-MDSCs. Mouse and human breast cancer including the triple negative
subset (TNBC) is one such cancer that efficiently expands PMN-MDSCs, which negatively correlates with clinical
outcomes in FDA-approved chemo-immunotherapy (CTx-I) protocols for a particular TNBC subset that
expresses PD-L1. Unfortunately, efforts to improve CTx-I strategies for PMN-MDSC inducing cancers by
therapeutically targeting these cells have proven unsuccessful. To this end, we found that our clinical-stage
immunotherapy drug called entolimod stimulates antitumor immunity against metastatic 4T1, a well-recognized
pre-clinical PD-L1+ TNBC tumor model that expands PMN-MDSCs. In fact, we found that entolimod stimulates
antitumor immunity against 4T1 in part by diminishing the immunosuppressive activity of PMN-MDSCs.
Moreover, mirroring the CTx-I protocols used to treat patients diagnosed with PD-L1+ TNBC, we found that
entolimod boosts antitumor efficacy of CTx-I against 4T1, albeit, through unresolved mechanisms. Despite these
findings in pre-clinical PD-L1+ TNBC, to what extent these findings translate to human PMN-MDSCs in breast
cancer patients and implications of these findings for boosting CTx-I in cancer patients remain unclear. Thus,
this proposal seeks to uncover the mechanistic underpinnings by which entolimod dampens PMN-MDSC activity
in both mice and humans in order to fuel the design of improved CTx-I therapies for those cancers in which
efficacy is hindered by PMN-MDSC expansion including PD-L1+ TNBC. And in this regard, entolimod has
successfully completed Phase I safety trials cumulatively involving nearly 200 subjects including healthy
volunteers and cancer patients thus facilitating the clinical translation of entolimod with CTx-I protocols.

## Key facts

- **NIH application ID:** 10355874
- **Project number:** 1R21CA267274-01
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Craig M. Brackett
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $235,901
- **Award type:** 1
- **Project period:** 2021-12-23 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355874

## Citation

> US National Institutes of Health, RePORTER application 10355874, Development of TLR5 agonist based approaches to boost chemo-immunotherapy by modulating immunosuppressive networks (1R21CA267274-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10355874. Licensed CC0.

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