# Genetically-engineered Bacteria Overcome Therapy Resistance

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $581,087

## Abstract

Project Summary:
For this proposal in response to PAR-22-085: Microbial-based Cancer Imaging and Therapy - Bugs as Drugs,
we will focus on metastatic pancreatic ductal adenocarcinoma (PDAC), for several reasons: PDAC is
particularly difficult to target and generally considered recalcitrant, but the pancreatic tumor microenvironment
(TME) features an abundance of tumor-associated macrophages (TAMs) and few T cells. Therefore, methods
to reprogram TAMs and enhance T-cell activation and proliferation will likely synergize with radiotherapy and
checkpoint immunotherapy to control local and metastatic disease.
 Bifidobacteria is a commensal that preferentially targets tumors, and oral Bifidobacteria has been found to
translocate from the gastrointestinal tract with subsequent homing to and replication specifically in tumors.
Building on these findings, we recently reported that systemically administered Bifidobacterium (i.v.)
specifically colonize and replicate in hypoxic tumor regions. Notably, we also found that i.v. administration of
Bifidobacterium also converted non-responding mice into responders, in the context of local immunotherapy
and/or ionizing radiation (IR). This data serves as proof-of-principle that systemic administration of
Bifidobacterium can enhance tumor control in combination with immunotherapy and/or IR.
 We have now successfully developed genetic tools to regulate gene expression in Bifidobacterium longum.
We propose to investigate the systemic administration of genetically-engineered Bifidobacterium delivering a
novel human IL-2 (SumIL2) to the TME in combination with radiotherapy and/or immunotherapy. This strategy
centers on harnessing both innate and adaptive pro-immune responses and is aimed at capitalizing on several
known mechanisms of tumor evasion. In addition, our plan to include a precise gene circuit for precise protein
secretion and bacteria self-destruction is a systemic therapeutic delivery innovation. Most importantly, we
anticipate that our approach using Bifidobacterium will elicit significant anti- tumor effects for several reasons:
1. Bifidobacterium is selectively taken up by tumors, and SumIL2 secretion is precisely controlled after bacteria
colonization, which will obviate the treatment-limiting toxicity commonly associated with IL-2 administration.
2. Our preliminary data presented here indicate that systemic (IV) administration of Bifidobacterium converts
non-responder mice into responders to anti-CD47 immunotherapy and radiotherapy.
3. In contrast to E. coli, Bifidobacterium is a human commensal anaerobic bacterium, giving our approach a
less toxic profile and more translational relevance.
 Our approach takes advantage of the natural features and genetic engineering of Bifidobacterium to
reinvigorate the immune suppressive TME via systemic injection, and thus could have broad applicability in
other hard-to-treat cancers.

## Key facts

- **NIH application ID:** 10944514
- **Project number:** 1R01CA292860-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Mark Mimee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $581,087
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944514

## Citation

> US National Institutes of Health, RePORTER application 10944514, Genetically-engineered Bacteria Overcome Therapy Resistance (1R01CA292860-01). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10944514. Licensed CC0.

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