# A Novel Microbiome-Based Immune-Modulator that Potentiates Cancer Checkpoint Therapy

> **NIH NIH R44** · RISE THERAPEUTICS, LLC · 2022 · $1,049,717

## Abstract

Project Summary
The goal of this project is to develop a novel oral drug, R-5780, which engages microbiome-associated Pattern
Recognition Receptors (PRRs) to enhance the activity of immune checkpoint inhibitor (ICI) therapy for the
treatment of cancer. R-5780 is based on a unique enzyme known as secreted antigen A (SagA) identified from
Enterococcus faecium which our research team showed can engage microbiome-associated immunological
pathways of the gut and potentiate the effects of PD-1 and CTLA4 pathway targeting agents [19, 29, 30].
Gut microbiota are associated with remarkable effects on host health and disease, and discrete species of
commensal bacteria have been correlated with improved patient responses to cancer immunotherapy [7-14]. The
molecular mechanisms underlying these beneficial bacterial effects remain poorly understood. In particular,
specific strains of Enterococci have been linked with improved response to anti-PD-1/PD-L1 treatment in
patients with metastatic melanoma, lung, and kidney cancers, but their mechanism of action has not been
elucidated nor employed to improve cancer immunotherapy. Recent work from our laboratory demonstrated
that these beneficial strains of Enterococci express the SagA peptidoglycan remodeling enzyme which, when
delivered recombinantly via a probiotic that does not endogenously express SagA, can potentiate the anti-
tumor effects of PD-1 checkpoint therapy in murine tumor model studies. The peptidoglycan metabolites
generated by SagA directly engage host PRRs activating key host immune signaling pathways [19].
While defined microbiome commensal strains may offer an interesting alternative to prevent and treat cancer in
combination with ICI therapy, many strains are not suitable for human use (including certain SagA positive
Enterococci), and the mechanism of action is difficult to characterize making drug development challenging.
However, recent studies suggest that improved probiotics engineered to carry specific recombinant biological
targeting agents to the gut can be an effective approach to target intestinal microbiome pathways. Indeed, our
recent results demonstrate that engineering or ‘reprogramming’ of probiotics to recombinantly express and
deliver SagA to the intestinal tract can impact immune responsiveness of cancer and greatly enhances the
effects of ICI therapy. These anti-tumor effects occur via intestinal PRR engagement. Our goal is to develop a
novel probiotic strain to deliver SagA (referred to as R-5780) as an orally administered drug that synergizes
with ICI agents to enhance effectiveness of immunotherapy. The key objectives of are to: 1) finalize R-5780
validation by determining activity in a second tumor model, and demonstrating preliminary manufacturability, 2)
perform necessary scale up process development to prepare for GMP manufacturing, 3) assess R-5780
activity in dose escalation studies and identify novel biomarkers that could be use in clinical trials, and 4)
complete ...

## Key facts

- **NIH application ID:** 10596291
- **Project number:** 4R44CA261509-02
- **Recipient organization:** RISE THERAPEUTICS, LLC
- **Principal Investigator:** Gary Fanger
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,049,717
- **Award type:** 4N
- **Project period:** 2021-04-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596291

## Citation

> US National Institutes of Health, RePORTER application 10596291, A Novel Microbiome-Based Immune-Modulator that Potentiates Cancer Checkpoint Therapy (4R44CA261509-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10596291. Licensed CC0.

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